endoplasmic reticulum proteostasis in glioblastoma from … · glioblastomas [gbms; world health...

19
CANCER 2017 © The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. Endoplasmic reticulum proteostasis in glioblastomaFrom molecular mechanisms to therapeutic perspectives Joanna Obacz, 1,2 * Tony Avril, 1,2 * Pierre-Jean Le Reste, 1,2,3 * Hery Urra, 4,5,6 Véronique Quillien, 1,2 Claudio Hetz, 4,5,6,7,8 Eric Chevet 1,2Cellular stress induced by the accumulation of misfolded proteins at the endoplasmic reticulum (ER) is a central feature of secretory cells and is observed in many tissues in various diseases, including cancer, diabetes, obesity, and neurodegenerative disorders. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that transmits information about the protein folding status at the ER to the cytosol and nucleus to restore proteostasis. In the past decade, ER stress has emerged as a major pathway in remodeling gene expression programs that either prevent transformation or provide selective advantage in cancer cells. Controlled by the formation of a dynamic scaffold onto which many regulatory compo- nents assemble, UPR signaling is a highly regulated process that leads to an integrated reprogramming of the cell. In this Review, we provide an overview of the regulatory mechanisms underlying UPR signaling and how this pathway modulates cancer progression, particularly the aggressiveness and chemotherapeutic resistance exhibited by glio- blastoma, a form of brain cancer. We also discuss the emerging cross-talk between the UPR and related metabolic processes to ensure maintenance of proteostasis, and we highlight possible therapeutic opportunities for targeting the pathway with small molecules. GliomasClinical, Cellular, and Molecular Issues Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form of primary brain tumors. Their incidence is thought to be about 3 per 100,000 each year. Standard treatment often includes maximal safe resection, followed by concomitant radiotherapy and chemotherapy with the use of temozolomide (TMZ), an alkylating agent (1). However, the highly infiltrative nature of this tumor, as well as its aggressiveness, leads to systematic failure of current therapeutics. Despite few improvements resulting from the development of second-line treatments such as antiangiogenic agents, the overall prognosis remains dismal and the median survival is 15 to 18 months (2). Furthermore, the neurological dysfunctions induced by tumor progression strongly impair the qual- ity of life of patients (3). Research for new treatments is active in the fields of cell and gene therapy and especially immunotherapy. The histopathologically defined entity glioblastomacovers a very heterogeneous tumoral population. Even if all GBMs share common morphological characteristics (such as proliferation of polymorphic glial cells, endothelial proliferation, necrosis, and vessel thrombosis), their stratification is being refined over the years through the knowledge of underlying pathogenesis ( 4). A first common distinction is made between so-called primary and secondary GBMs. Primary GBMs are considered to arise de novo as grade IV tumors, whereas secondary GBMs arise from the natural evolution of lower-grade tumors (astrocytomas or oligodendrogliomas; WHO grades II and III). Even if their cellular behavior is ultimately the same, they present with activation of dif- ferent oncogenic pathways. Primary GBMs commonly show ampli- fication or mutation of EGFR and loss or mutation of NF1, PTEN, RB1, CDKN2A, or CDKN2B or mutations in the TERT promoter (5). The molecular hallmark of secondary GBMs is the presence of muta- tions in IDH1 or IDH2, a signature for most of the lower-grade gliomas and a good prognostic factor. The progression from low- to high-grade gliomas involves loss of RB1 or CDKN2A (as in primary type) and amplification of PDGFRA, along with alterations related to the original glial cell lineage (mutations in TP53 or ATRX in astrocytomas, codele- tion of chromosomes 1p and 19q, or methylation of the TERT promoter in oligodendrogliomas) (5). Along with this classical subdivision, genomic-based clustering has highlighted four subgroups of GBM: proneural (characterized by PDGFRA and IDH mutations, or TP53 mutations), neural (characterized by expression of neuronal markers), classical (characterized by gain of chromosome 7, loss of chromosome 10, or EGFR amplification), and mesenchymal (characterized by mu- tation of NF1 and expression of YL40 and CD44). Each shows differ- ent clinical and radiological features as well as varied responses to treatment (5). Even if GBMs are nowadays treated in a relatively aspe- cific manner, these classifications might constitute the basis for more individualized therapeutics. The individual susceptibility to chemotherapy emerged with the knowledge of the impact of methylation in the promoter of the gene encoding O 6 -methylguanine-DNA methyltransferase (MGMT). MGMT is a protein that contributes to DNA repair and partially counters the effects of alkylating agents such as TMZ (6). The methylation of its gene promoter, found in the tumors of less than half of GBM patients, is as- sociated with greater chemosensitivity and a better prognosis than in patients whose tumors lack MGMT promoter methylation. Because it has a direct impact on the choice of treatment (radiotherapy versus TMZ), assessment of MGMT promoter methylation has been included 1 INSERM U1242, Chemistry, Oncogenesis, Stress Signaling, Université de Rennes 1, Rennes 35000, France. 2 Centre de Lutte Contre le Cancer Eugène Marquis, Rennes 35042, France. 3 Department of Neurosurgery, University Hospital Pontchaillou, Rennes 35000, France. 4 Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile, Santiago, Chile. 5 Center for Geroscience, Brain Health and Metabolism, Santiago, Chile. 6 Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, 1027 Independencia, P.O. Box 70086, Santiago, Chile. 7 Buck Institute for Research on Aging, Novato, CA 94945, USA. 8 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA. *These authors contributed equally to this work. Corresponding author. Email: [email protected] SCIENCE SIGNALING | REVIEW Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017 1 of 18 on March 7, 2021 http://stke.sciencemag.org/ Downloaded from

Upload: others

Post on 12-Oct-2020

0 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

SC I ENCE S I GNAL ING | R EV I EW

CANCER

1INSERM U1242, Chemistry, Oncogenesis, Stress Signaling, Université de Rennes 1,Rennes 35000, France. 2Centre de Lutte Contre le Cancer Eugène Marquis, Rennes35042, France. 3Department of Neurosurgery, University Hospital Pontchaillou, Rennes35000, France. 4Faculty of Medicine, Biomedical Neuroscience Institute, University ofChile, Santiago, Chile. 5Center for Geroscience, Brain Health and Metabolism, Santiago,Chile. 6Program of Cellular and Molecular Biology, Center for Molecular Studies of theCell, Institute of Biomedical Sciences, University of Chile, 1027 Independencia, P.O. Box70086, Santiago, Chile. 7Buck Institute for Research on Aging, Novato, CA 94945, USA.8Department of Immunology and Infectious Diseases, Harvard School of Public Health,Boston, MA 02115, USA.*These authors contributed equally to this work.†Corresponding author. Email: [email protected]

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

2017 © The Authors,

some rights reserved;

exclusive licensee

American Association

for the Advancement

of Science.

Dow

nloaded fr

Endoplasmic reticulum proteostasis inglioblastoma—From molecular mechanismsto therapeutic perspectivesJoanna Obacz,1,2* Tony Avril,1,2* Pierre-Jean Le Reste,1,2,3* Hery Urra,4,5,6 Véronique Quillien,1,2

Claudio Hetz,4,5,6,7,8 Eric Chevet1,2†

Cellular stress induced by the accumulation of misfolded proteins at the endoplasmic reticulum (ER) is a centralfeature of secretory cells and is observed in many tissues in various diseases, including cancer, diabetes, obesity, andneurodegenerative disorders. Cellular adaptation to ER stress is achieved by the activation of the unfolded proteinresponse (UPR), an integrated signal transduction pathway that transmits information about the protein foldingstatus at the ER to the cytosol and nucleus to restore proteostasis. In the past decade, ER stress has emerged asa major pathway in remodeling gene expression programs that either prevent transformation or provide selectiveadvantage in cancer cells. Controlled by the formation of a dynamic scaffold onto which many regulatory compo-nents assemble, UPR signaling is a highly regulated process that leads to an integrated reprogramming of the cell. Inthis Review, we provide an overview of the regulatory mechanisms underlying UPR signaling and how this pathwaymodulates cancer progression, particularly the aggressiveness and chemotherapeutic resistance exhibited by glio-blastoma, a form of brain cancer. We also discuss the emerging cross-talk between the UPR and related metabolicprocesses to ensure maintenance of proteostasis, and we highlight possible therapeutic opportunities for targetingthe pathway with small molecules.

hom

on M

arch 7, 2021ttp://stke.sciencem

ag.org/

Gliomas—Clinical, Cellular, and Molecular IssuesGlioblastomas [GBMs; World Health Organization (WHO) grade IVgliomas] represent the most frequent and malignant form of primarybrain tumors. Their incidence is thought to be about 3 per 100,000each year. Standard treatment often includes maximal safe resection,followed by concomitant radiotherapy and chemotherapy with the useof temozolomide (TMZ), an alkylating agent (1). However, the highlyinfiltrative nature of this tumor, as well as its aggressiveness, leads tosystematic failure of current therapeutics. Despite few improvementsresulting from the development of second-line treatments such asantiangiogenic agents, the overall prognosis remains dismal and themedian survival is 15 to 18 months (2). Furthermore, the neurologicaldysfunctions induced by tumor progression strongly impair the qual-ity of life of patients (3). Research for new treatments is active in thefields of cell and gene therapy and especially immunotherapy.

The histopathologically defined entity “glioblastoma” covers a veryheterogeneous tumoral population. Even if all GBMs share commonmorphological characteristics (such as proliferation of polymorphic glialcells, endothelial proliferation, necrosis, and vessel thrombosis), theirstratification is being refined over the years through the knowledge ofunderlying pathogenesis (4). A first common distinction is made betweenso-called primary and secondary GBMs. Primary GBMs are consideredto arise de novo as grade IV tumors, whereas secondary GBMs arise

from the natural evolution of lower-grade tumors (astrocytomas oroligodendrogliomas; WHO grades II and III). Even if their cellularbehavior is ultimately the same, they present with activation of dif-ferent oncogenic pathways. Primary GBMs commonly show ampli-fication or mutation of EGFR and loss or mutation of NF1, PTEN,RB1, CDKN2A, or CDKN2B or mutations in the TERT promoter (5).The molecular hallmark of secondary GBMs is the presence of muta-tions in IDH1 or IDH2, a signature for most of the lower-grade gliomasand a good prognostic factor. The progression from low- to high-gradegliomas involves loss of RB1 or CDKN2A (as in primary type) andamplification of PDGFRA, along with alterations related to the originalglial cell lineage (mutations in TP53 or ATRX in astrocytomas, codele-tion of chromosomes 1p and 19q, or methylation of the TERT promoterin oligodendrogliomas) (5). Along with this classical subdivision,genomic-based clustering has highlighted four subgroups of GBM:proneural (characterized by PDGFRA and IDH mutations, or TP53mutations), neural (characterized by expression of neuronal markers),classical (characterized by gain of chromosome 7, loss of chromosome10, or EGFR amplification), and mesenchymal (characterized by mu-tation of NF1 and expression of YL40 and CD44). Each shows differ-ent clinical and radiological features as well as varied responses totreatment (5). Even if GBMs are nowadays treated in a relatively aspe-cific manner, these classifications might constitute the basis for moreindividualized therapeutics.

The individual susceptibility to chemotherapy emerged with theknowledge of the impact of methylation in the promoter of the geneencoding O6-methylguanine-DNA methyltransferase (MGMT). MGMTis a protein that contributes to DNA repair and partially counters theeffects of alkylating agents such as TMZ (6). The methylation of its genepromoter, found in the tumors of less than half of GBM patients, is as-sociated with greater chemosensitivity and a better prognosis than inpatients whose tumors lack MGMT promoter methylation. Because ithas a direct impact on the choice of treatment (radiotherapy versusTMZ), assessment of MGMT promoter methylation has been included

1 of 18

Page 2: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

CREDIT:A.KITTE

RMAN/SCIENCESIGNALING

SC I ENCE S I GNAL ING | R EV I EW

in clinical practice for patients over 65 years old. Other interesting mu-tations and targets have been identified, such as BRAF mutations, buttheir incidence and therapeutic impact are relatively small. In recentyears, a growing body of evidence implicates cellular stress response al-terations in the pathogenesis and therapeutic resistance of GBM. Alteredprotein homeostasis (referred to as proteostasis) at the level of the endo-plasmic reticulum (ER), the first compartment of the secretory pathwayand the site of secretory and transmembrane protein biogenesis, lipidsynthesis, and calcium storage, and the signaling pathways engaged totrigger cellular adaptation to ER stress are emerging as relevant drivers ofinitiation, growth, and chemoresistance in multiple tumor types. Pro-teostasis pathways are proposed as relevant players in the crossroad be-tween many mutational and metabolic processes, representing a highlypromising therapeutic target, the tenants of which being discussed fur-ther in this Review.

http://stke.sciencD

ownloaded from

ER Proteostasis and Stress Signaling—GeneralitiesTo propagate and activate pro-oncogenic signaling pathways, cancercells exhibit high demand for protein synthesis and folding comparedto nonmalignant cells (7, 8). Moreover, these cells are constantly ex-posed to both intrinsic stresses (such as genomic instability, increasedmetabolic burden, and oncogene expression) (9, 10) and extrinsicstresses (including hypoxia, oxidative stress, and nutrient deprivation)(11), which increase the risk of protein misfolding and may perturbproteostasis. In normal and tumor cells, the ER operates as a specializedcompartment to control the biogenesis of secretory and transmembraneproteins. Within the ER lumen, a subset of chaperones and foldasesensures the correct protein folding, thus maintaining ER proteostasis(12). However, if the protein folding demand exceeds ER folding and

on March 7, 2021

emag.org/

clearance capacities, then misfolded proteinsaccumulate in this compartment, therebygenerating ER stress (13). To restore ER pro-teostasis, cells trigger an adaptive mecha-nism, known as unfolded protein response(UPR), through the activation of three ERtransmembrane protein sensors: inositol-requiring enzyme 1a (hereafter referred toas IRE1), activating transcription factor 6a(hereafter referred to as ATF6), and proteinkinase R–like ER kinase (PERK) (Fig. 1)(14). Under basal conditions, all three sen-sors (IRE1, ATF6, and PERK) are kept intheir inactive state through the associationwith the ER-resident glucose-regulated pro-tein 78 (GRP78); however, upon ER stress,the association is disrupted and the UPRsignal transduction cascade commences(15). Subsequently, IRE1 forms a functionalmultimer with both serine/threonine kinaseand endoribonuclease (RNase) activities inits cytoplasmic domain (16). The RNase do-main in IRE1 mediates the cleavage of 26-nucleotide intron from the mRNA encodingX-box binding protein 1 (XBP1) and, withcoordinated intervention from the catalyticsubunit of the transfer RNA–splicing ligasecomplex (RTCB), generates a spliced transcriptthat is translated into an active transcription

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

factor named XBP1s (17). In addition, IRE1 participates in the degra-dation of various mRNAs and microRNAs (miRNAs) in a processcalled regulated IRE1-dependent decay (RIDD) (18). ER stress alsotriggers the translocation of ATF6 from the ER membrane to the Golgiapparatus, where it is cleaved into its active form, ATF6f, by site1 and 2 proteases (SP1 and SP2) (16). ATF6f is further transported tothe nucleus to promote expression of its UPR-related downstream genes(19). Last, after GRP78 disassociation, activated PERK dimerizes, auto-transphosphorylates, and phosphorylates the eukaryotic translation ini-tiation factor 2a (eIF2a), which results in decreased general translationwith increased translation of ATF4 and ATF4-dependent transcriptionof various ER stress regulators (10). Activation of the three UPRbranches increases cellular antioxidant capacities, hindering the globalprotein synthesis and enhancing the expression of chaperonesand ER quality control proteins to reinforce protein folding and theER-associated degradation (ERAD) pathway (20). However, if ER pro-teostasis cannot be restored, then cell apoptosis is triggered (21).

Constitutive activation of UPR signaling has been observed inmany types of human tumors including breast cancers, GBM, lympho-ma, myeloma, and various adenocarcinomas (22–28). In addition, ac-tivation of all the UPR branches was described in cellular and animalmodels of BRAF-, RAS-, MYC-, RET-, or HER2-driven tumorigenesis[reviewed in (29)]. Overexpression of the key regulator of ER stressresponse GRP78 was also frequently reported in tumor tissues andwas associated with reduced patient survival (30–32). The concept ofER proteostasis addiction has been proposed as a mechanism support-ing tumor growth and malignant cell transformation (33). It is nowwidely acknowledged that cancer cells may exploit the prosurvivalsignals of the UPR to cope with both intrinsic and extrinsic stressesand escape apoptosis as well as modulate other disease-associated

Nucleus

PERKAntioxydation

Amino acidmetabolism

ATF6ERAD

Folding/quality control

Endoplasmicreticulum

Cytoplasm

Golgicomplex

Cleavage

PERK IRE1

RIDD

Splicing

miRNA

mRNA

RTCB

Translation

Misfoldedproteins

GRP78

PDIA6

CHOP

GADD34

PP1c ATF4 XBP1s

JNK

ATF6f

NRF2 NRF2 eIF2α eIF2α

PDIA5

ATF6

UPR targetgenes

P

IRE1Secretion

Autophagy

Apoptosis

Lipid synthesis

S1P/S2P

Fig. 1. The three arms of the UPR. All three ER stress sensors (PERK, IRE1, and ATF6) initially activate signalingevents that increase protein-folding capacity and reduce protein load on the ER. These transcriptional andtranslational outputs (listed in the nucleus under the respective ER stress sensor–mediated pathway) tend toreestablish protein-folding homeostasis in the ER and promote cell survival. JNK, c-Jun N-terminal kinase.

2 of 18

Page 3: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

SC I ENCE S I GNAL ING | R EV I EW

processes including migration, invasion, angiogenesis, and inflam-mation [reviewed in (33, 34)]. Overall, accumulating evidence indi-cates that UPR signaling modulates almost all hallmarks of cancer(34). In the next section, we will briefly contextualize the contributionof each arm of the UPR to selected cancer hallmarks.

on March 7, 2021

http://stke.sciencemag.org/

Dow

nloaded from

UPR Signaling and the Hallmarks of CancerPERKRecent data pertaining to tissues and tumors of the gastrointestinaltract suggest that PERK/eIF2a pathway plays a crucial role in cancerinitiation through the regulation of cell stemness (35, 36). Moreover,ablation of PERK increases oxidative stress, impairs cell proliferation,and promotes G2/M cell cycle delay in breast cancer models (37).PERK-mediated protection of tumor cells from apoptosis under hypox-ia is also observed both in culture and in animal models (29). Throughthe activation of autophagy and the antioxidant response, PERK facil-itates survival of cells experiencing anoikis, a form of programmed celldeath induced when they detach from the surrounding extracellularmatrix (38). PERK activation is also associated with tumor dormancyand resistance to therapy (39), as well as invasion and metastasis bybreast cancer cell lines in culture and in vivo, respectively (40). In breastcancer models, expression of epithelial-to-mesenchymal transition–related genes was found to correlate with that of the PERK downstreamtarget ATF4 (40). Activation of the PERK/eIF2a/ATF4 axis may pro-mote metastasis through the up-regulation of the metastasis-associatedLAMP3 gene (41) or induction of matrix metalloproteinases MMP2and MMP7 (42). Through the direct binding to the VEGFA genepromoter, ATF4 also increases angiogenesis in tumors (43). Moreover,either pharmacological inhibition or engineered knockdown of PERKattenuates tumor growth and significantly reduces blood vessel densityin mouse models (43, 44). PERK-mediated inhibition of proteintranslation also reduces the inhibitor of kB (IkB) to nuclear factor kB(NF-kB) ratio, enabling the translocation of NF-kB to the nucleus andtranscription of its downstream inflammatory genes (45).

IRE1The gene encoding the stress sensor IRE1 is sometimes (although notfrequently) mutated in cancer and is potentially involved in tumori-genesis (46). Recent data suggest that somatic mutations alter thesignaling properties of IRE1 (47). Accumulating evidence links IRE1signaling with various aspects of cancer biology. For instance, combi-nation of an IRE1 RNase inhibitor with either bortezomib (a protea-some inhibitor) or arsenic trioxide (AS2O3) precluded XBP1 mRNAsplicing and alleviated acute myeloid leukemia cell growth (48). TheIRE1/XBP1 axis has been also implicated in decreased sensitivity oftransformed cells to hypoxia-induced death (49). Moreover, a directinteraction between XBP1s and hypoxia-inducible factor 1a (HIF1a),a master regulator of tumor cell response to hypoxia, reportedly reg-ulate the expression of aggressiveness-associated genes VEGFA, PDK1,or GLUT1, among others, in triple-negative breast cancers (TNBCs)(50). The role of IRE1 in metastasis remains ambiguous; in normalepithelial cells, IRE1 enhances cell migration (51), whereas in gliomaIRE1 inhibits tumor cell invasion (52). Moreover, in TNBC, silencingXBP1 decreased the formation of lung metastases (50). IRE1 signalingis also involved in the regulation of angiogenesis and protumorigenicinflammation. IRE1 interacts with tumor necrosis factor (TNF) recep-tor–associated factor 2 (TRAF2) to phosphorylate IkB, thus activatingNF-kB signaling (53). XBP1s also binds to the VEGFA promoter and

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

regulates its transcription in response to ER stress (43, 54). Further-more, it was demonstrated that mouse embryonic fibroblasts lackingIRE1 expression were unable to induce VEGFA expression upon is-chemia and, when transplanted into immunodeficient mice, generatedtumors with reduced vascularization compared to their control coun-terparts (55). In addition, IRE1 also regulates secretion of vascularendothelial growth factor A (VEGFA), interleukin-6 (IL-6), andIL-1b (52). Thus, IRE1 appears to be an important regulator of tu-mor progression by regulating several hallmarks of cancer: migra-tion, tolerance to hypoxia, inflammation, and angiogenesis.

ATF6Our understanding of the consequence(s) of ATF6 activation in tu-mors is currently limited. So far, it has been demonstrated thatATF6 is required for the adaptation of dormant squamous carcinomacells to nutritional stresses and in vivo microenvironment through theup-regulation of RHEB and activation of mTOR signaling (56). More-over, as shown in the hepatocellular carcinoma model, ATF6 may beinvolved in the regulation of cell proliferation (57) or in the sensitivityto chemotherapy in leukemia cells (58). Data also suggest ATF6 con-tribution to cancer progression by shaping tumor microenvironment(59) as well as in the induction of the senescent phenotype (60). Insummary, accumulating evidence suggests that activation of theUPR may affect multiple aspects related to cancer progression beyondits classical role in tumor adaptation against hypoxia.

ER Proteostasis Control in GBM—Molecular andCellular ImpactsUPR-induced transcription factors controlcell survival or deathIn situations where ER stress is not alleviated, UPR sensors redirecttheir downstream signals toward apoptosis (Fig. 2). The C/EBP ho-mologous protein (CHOP) is a major proapoptotic transcription factortriggered by UPR that suppresses antiapoptotic outer mitochondrialmembrane protein BCL2 (B cell lymphoma 2) and induces proapop-totic proteins such as death receptor 5 (DR5) and ER oxidoreductin–like protein 1a (ERO1a) (61–64). In GBM cell culture models, numer-ous anticancer drugs were shown to induce CHOP expression. Forinstance, CHOP is up-regulated in tumor cell lines exposed to TMZ(22). TMZ also up-regulates the expression of GRP78, which suppressesthe proapoptotic activity of CHOP (22). However, combined use ofbortezomib and celecoxib [a cyclooxygenase 2 (COX2) inhibitor], bothER stress inducers, up-regulates GRP78 and CHOP expression and ac-tivates JNK, caspase-3, caspase-4, caspase-7, and caspase-9, leading toGBM cell death (65). The cisplatin-derived anticancer drug, ruthenium-derived compound 11 (RDC11), also induces CHOP and GRP78.RDC11-induced CHOP activation is associated with the up-regulationof proapoptotic downstream molecules, Tribbles homolog 3 (TRB3)and ChaC glutathione-specific g-glutamylcyclotransferase 1 (CHAC1)(66). Nelfinavir (a drug belonging to protease inhibitor class), when com-bined with TNF-related apoptosis-inducing ligand (TRAIL), increasesGBM apoptosis through CHOP and DR5 up-regulation (67). Finally,IRE1 activation is also involved in GBM cell apoptosis induced by anitric oxide (NO) donor, S-nitroso-N-acetyl penicillamine, leading tothe activation of TRAF2 and JNK and the phosphorylation of CREB,a transcription factor involved in NO-mediated cell death (68). Collect-ively, this shows that, in GBM cells, UPR-induced transcription factorscan control both prosurvival and prodeath mechanisms.

3 of 18

Page 4: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

CREDIT:A.KITTE

RMAN/SCIENCESIGNALING

SC I ENCE S I GNAL ING | R EV I EW

on March 7, 2021

http://stke.sciencemag.org/

Dow

nloaded from

UPR-induced transcription factors incancer-associated signalingRecent studies underline the complexity of the UPR downstreampathways that also trigger other specific transcription factors, thusregulating tumor survival and growth (Fig. 2). Besides the ability toinduce cell death, CHOP activation also triggers the protumoral in-flammatory response through caspase-11 activation and release ofIL-1b (69). In GBM cells, IRE1-mediated JNK activation inducesepiregulin (EREG), a ligand for the epidermal growth factor receptor(EGFR) family member ERBB1, which contributes to an autocrineproliferation loop through EGFR signaling (70). Neovascularizationis critical for cancer progression to overcome local changes in tumormicroenvironment that limit resources in oxygen and nutrients. Aconnection between IRE1, PERK, and angiogenesis is observed in sev-eral tumor cell types, including breast and brain cancers as well ashead and neck squamous and lung carcinomas (43, 55). In GBM,IRE1 appears as a major regulator of invasion and angiogenesis(71). IRE1 RNase activity targets the mRNA of SPARC, a secreted ma-tricellular protein that regulates the interaction between GBM cells andextracellular matrix, promoting GBM cell migration (72). Through ox-ygen or glucose deprivation–induced ER stress in GBM cells, IRE1 ac-tivation also leads to increased expression of VEGFA, which encodes acritical factor of tumor angiogenesis (55). Moreover, IRE1 up-regulatesthe genes encoding various proangiogenic factors, such as the interleu-kins IL-1b, IL-6, and IL-8, and down-regulates antiangiogenic factors,such as thrombospondin 1 (THBS1) and decorin, promoting GBM an-giogenesis (52). In addition to the activation of the ER stress–induced

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

ATF4 pathway, PERK also supports prosurvival signals under oxida-tive stress. PERK activation triggers dissociation of the cytoplasmicKelch-like ECH-associated protein 1 (KEAP1)/NRF2 complex, leadingto the release and translocation of NRF2 to the nucleus (73). In GBM,PERK also controls ceramide production that is critical for calcium in-duction and reactive oxygen species (ROS) generation, which in turnpromotes autophagy and cell death (74). PERK-mediated activation ofATF4 leads to the increase of proangiogenic factors such as VEGF,FGF2, and IL-6 and to the decrease in antiangiogenic factors THBS1,CXCL14, and CXCL10 in a HIF1a-independent manner (43). ThePERK and ATF6 arms of the UPR also induce ADAM17, a memberof the ADAM (a disintegrin and metalloproteinase) family that is as-sociated with tumor initiation and progression (75). In other brain tu-mors such as medulloblastoma, PERK activation increases VEGFAexpression and is associated with enhanced cell migration throughVEGFR2 signaling (76). However, no evidence has been reported sofar that PERK promotes GBM angiogenesis and invasion. Recently,the involvement of the ATF6 arm of the UPR has been described inGBM resistance to radiation (77). Irradiation of GBM cells leads to UPRinduction with a clear involvement of ATF6-dependent up-regulationof GRP78 and NOTCH1 (77). Moreover, a high-resolution clusteredregularly interspaced short palindromic repeats (CRISPR) screen inGBM stem-like cells has also revealed the involvement of ATF6 branchof the UPR in glioma development (78). Together, each UPR armaffects the balance of pro- and antitumor signaling pathways that isintegrated by tumor cells and leads to a complete cell adaption toits adverse microenvironment. In summary, the signals triggered by

PERKIRE1

Proliferation Inflammation Immunesuppression

Invasion andmetastasis

Resistanceto growth

suppressors

Cell survival Angiogenesis

CHOP XBP1sASK1JNK

C-JunAP1

Per1

CXCL3 E2Fcyclin D

EREG

CREBPUMABim

EROαNoxa

CHAC1Bcl2 casp11

SKIP3DR5

Per1

CXCL3CXCL14CXCL10

DCNTHBS1

FGF6IL6, IL8VEGFA

GSTANQO1

SPARC ADAM17IL1β

HIF1α

ATF4

ATF6f

NF-κBmTOR

NRF2

ATF6

TRAF2

ATF3

p38

MAP

K S1P

S2P

eIF2α

P

†×†

Fig. 2. The transcription factor network associated with the arms of the UPR. All three ER stress sensors (PERK, IRE1, and ATF6) activate downstream signalingevents that directly affect cancer biology. The pathways underlined in black have been described in human GBM. Arrows, positive regulation; dot-end, negativeregulation; AP1, activator protein 1; ASK1, apoptosis signal–regulating kinase 1; BIM, Bcl-2 interacting mediator of cell death; casp11, caspase 11; CREB, cyclic adenosinemonophosphate responsive element binding protein; CXCL, C-X-C motif chemokine ligand; DCN, decorin; FGF6, fibroblast growth factor 6; GSTA, glutathione S-transferasealpha; mTOR, mechanistic target of rapamycin; NQO1, NAD(P)H quinone dehydrogenase 1; SKIP3, SKP1-interacting partner 3.

4 of 18

Page 5: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

SC I ENCE S I GNAL ING | R EV I EW

on March 7, 2021

http://stke.sciencemag.org/

Dow

nloaded from

ER stress also involve major cancer-related transcription factors thatin turn control tumor phenotypes.

UPR-mediated modulation of gene transcription throughchromatin structure remodelingVery little is known about the role of epigenetic modulation and theUPR in GBM. However, recent studies have shown the existence offunctional links between the UPR and epigenetic regulators, therebyleading us to postulate that these links could also play a role in GBM.UPR-mediated gene expression also involves chromatin remodeling bydirectly acting on histone modifications. For instance, the gene encod-ing Jumonji domain–containing 3 histone lysine demethylase [JMJD3;also known as lysine (K)–specific demethylase 6B (KDM6B)] is anATF4 target gene (79). Moreover, chaetocin (a nonspecific inhibitorof histone lysinemethyltransferases) increasesATF3 andCHOP expres-sion, leading to DR5-dependent apoptosis of lung cancer cells (80),thereby linking ER stress to epigenetic regulation. HDACs and histoneacetyltransferases (HATs) are other enzymes that modify the acetyla-tion status of histones, key molecules of the chromatin architecture.HDAC1 was shown to directly interact with PERK-induced ATF3,leading to epigenetic suppression of EGR1 expression (81), whereasHDAC4 was reported to interact with ATF4, preventing its trans-location to the nucleus and consequently inhibiting the up-regulationof CHOP and ER stress–mediated apoptosis (82). Furthermore,HDAC1 binds to the GRP78 promoter to repress its expression underbasal conditions but not during ER stress (83). Finally, SIRT1 inhibitsXBP1s transcriptional activity through its deacetylation (84). In contrasttoHDACs, the Spt-Ada-Gcn5-acetyltransferase (SAGA)HAT complexis essential for ER stress–induced gene transcription (85). For instance,ATF6 activates transcription of ER stress response genes through therecruitment of several HAT complexes including SAGA and Ada2a-containing (ATAC) molecules (86, 87). Transcription of ATF4 targetgenes CHOP, ATF3, and JMJD3 requires HAT activity (79). UnderER stress, the SAGA complex increases acetylation of the histoneH3K14 and maintains trimethylation of histone H3K4 on ER stress–induced genes, thus allowing their transcription (88). Two HATs,p300/CREB-binding protein–associated factor [PCAF; also known asK (lysine) acetyltransferase 2B (KAT2B)] or “general control nonde-repressible 5” (GCN5; also known as KAT2A), either act as coactivatorsin XBP1s transcriptional function (89) or acetylate XBP1s to enhanceits nuclear retention and stability (90), respectively. PCAF also stabilizesATF4 by inhibiting its ubiquitination and increases its transcriptionalactivity in an acetylation-independent manner (91). Data in braincancers are scarcer. In neuroblastoma, acetylation of RTN-1C, whichencodes an ER-associated protein belonging to the reticulon family, in-hibits HDAC1, thereby regulating the expression of ER stress genes (92,93). In neural and GBM stem cells, the polycomb complex protein Blymphoma Mo-MLV insertion region 1 homolog (BMI1) controls ex-pression of tumor suppressor genes such as ATF3 and CBX7 that be-long to transforming growth factor b (TGFb)/bone morphogeneticprotein (BMP) and ER stress pathways (94). However, evidence of adirect link between UPR sensors and BMI1 requires further investi-gation. Together, these data show an intricate epigenetic network thatregulates ER stress–induced transcription through both chromatin re-modeling and posttranslational modification (Fig. 3). Because gen-eral epigenetic mechanisms have been described to playinstrumental roles in GBM, further exploration of the existing linksbetween UPR signaling and epigenetic regulation in these tumorsis justified.

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

Posttranscriptional cell reprogramming toward adaptationPosttranscriptional regulations induced by the UPR can occur at sev-eral levels. First, gene expression can be regulated through modulationof mRNA stability; as such, miRNA can represent effective regulatorytools. The biogenesis and stability of some miRNAs are observed to beunder the control of the UPR either at the transcriptional level (95) orat the posttranscriptional level through IRE1-mediated degradation(96). Recent advances in this area have demonstrated that more than10 miRNAs are regulated at the transcriptional level upon activationof the three branches of the UPR and that those miRNAs exhibitedselectivity toward each individual branch (97). This was illustrated inGBM in which three of the four direct targets of IRE1 RNase (96) arederegulated, namely, miR-17, miR-34a, and miR-96. As such, the abun-dance of miR-17 is increased in irradiated GBM stem cells (98), theabundance of miR-34a, which plays a tumor suppressor role by target-ing multiple oncogenes, is decreased in GBM (99), and the abundanceof miR-96 is increased in GBM and promotes tumor growth bycontributing to the activation of the WNT/b-catenin pathway (100).The second level of posttranscriptional regulation is mediated by thedirect control of mRNA stability through mechanisms depending onIRE1 and named RIDD (101). RIDD controls mRNA expression pro-files through direct cleavage at a conserved site bearing the CUGCAGsequence in a P-loop structure (18). RIDD in GBM has been illustratedin many instances. For example, the stability of both SPARC mRNA(72), whose translation product has been involved in the control of tu-mor cell migration and invasion, and PERIOD1 (PER1) mRNA (102),whose translation product is involved in repressing proinflammatorycytokine expression, is decreased. Although many RIDD substrateswere identified, the precise mechanisms associated with RIDD selectiv-ity and physiological or pathological relevance remain to be fully elu-cidated. The third level of posttranscriptional regulation is mediated bytranslational and posttranslational control. Upon activation of the UPR,both PERK and IRE1 can directly affect (i) protein abundance throughinactivation of the translation initiation complex through the phospho-rylation of eIF2a or through the degradation of ribosomal RNA, re-spectively (103), and (ii) protein phosphorylation status. However,both mechanisms have not been linked directly to GBM developmentand thus require more in-depth investigations.

ER proteostasis control in glioma stromal cellsGliomas represent highly complex tumors consisting of various non-neoplastic stromal cells, such as tumor-associated brain endothelialcells, myeloid dendritic cells (DCs), plasmacytoid DCs, T cells, as wellas tumor-associated macrophages and microglia (TAMs) (104, 105).TAMs are predominant glioma-infiltrating immune cells, whichmay comprise up to 30% of the tumor mass (106). In many typesof cancer, increased TAM infiltration correlates with high histologicalgrade and poor patient outcome (107, 108). Two populations ofmacrophages have been distinguished: classically activated (M1 phe-notype) macrophages, which produce inflammatory and immune-stimulating cytokines to elicit the adaptive immune response againsttransformed cells, and alternatively activated (M2 phenotype) macro-phages, which have tumor-supportive properties (109, 110). In estab-lished tumors, TAMs resemble M2-like macrophages (111) and theyfacilitate tumor growth and survival, induce the “angiogenic switch,”suppress the adaptive immune response, and remodel extracellularmatrix to promote metastasis [reviewed in (110, 112, 113)]. In line,it was demonstrated that TAMs isolated from postoperative tissuespecimens of glioma patients lacked expression of the costimulatory

5 of 18

Page 6: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

CREDIT:A.KITTE

RMAN/SCIENCESIGNALING

SC I ENCE S I GNAL ING | R EV I EW

on March 7, 2021

http://stke.sciencemag.org/

Dow

nloaded from

molecules CD86, CD80, and CD40 that are critical for T cell activa-tion and hence lost their ability to produce proinflammatory cyto-kines (including TNFa, IL-1, or IL-6) (104), therefore exhibiting animmunosuppressive phenotype. A large body of evidence demon-strates that the UPR may also contribute to cancer progression byshaping the tumor microenvironment (Fig. 4). Activation of IRE1or XBP1, PERK, and CHOP in macrophages promotes the produc-tion of protumorigenic cytokines IL-6 and TNFa (114, 115), and inDCs, CHOP promotes the production of proinflammatory IL-23,thereby favoring tumor growth (116). Similarly, deletion of ER-residentchaperone GRP96 in macrophages significantly reduced the abun-dance of IL-17A, IL-17F, IL-23, and TNFa in tumor-bearing mice(117). In addition, Mahadevan and colleagues demonstrated thatconditioned media from ER-stressed tumor cells triggered the globalER stress response in the recipient macrophages and DCs, whichwas manifested by the transcriptional up-regulation of GRP78, XBP1s,and CHOP (118, 119). These cells also up-regulated the transcription ofthe proinflammatory cytokines IL-6 and IL-23p19 (a subunit of IL-23)and secreted large amounts of IL-6, IL-23, and TNFa, as well as mac-rophage inflammatory protein 1a (MIP1a), MIP1b, and monocytechemoattractant protein 1 (MCP1) (118, 119).

Evidence also suggests that the UPR may blunt the antitumor im-mune response by affecting antigen presentation and antigen-presentingcells per se. Perturbation of the secretory pathway or ER stress decreasesthe presentation of high-affinity peptides by major histocompatibilitycomplex (MHC) classes I and II (120, 121). Moreover, UPR-dependentproducts that transfer from cancer cells to DCs trigger arginase activa-tion (an enzyme that suppresses T cell function) (122) and hinder theability of DCs to cross-present antigen and cross-prime CD8+ T cells

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

(119). Those CD8+ T cells also up-regulatedthe abundance of IL-2, IL-10, and FOXP3and concomitantly down-regulated thatof CD28, which indicates a suppressivephenotype (119). Notably, in DCs, IRE1is constitutively activated and its down-stream target XBP1s is abundant, evenin the absence of ER stress (123). Further,loss of XBP1 promotes defects in DCphenotype and antigen presentation, whichwas mediated by RIDD of mRNAs encod-ing CD18 integrins and components ofMHC class I machinery, such as tapasin(123). XBP1 reportedly promotes the de-velopment and survival of DCs (124).

The UPR is also involved in the cross-talk between tumor cells and endothelialcells. Upon binding to VEGFR on endo-thelial cells, VEGF activates the UPR sen-sors through the phospholipase Cg (PLCg)pathway without accumulation of mis-folded proteins in the ER (59). This, inturn, promotes endothelial cell survival inan AKT-dependent manner and inducesangiogenesis in mouse models (59). Inaddition, more recent work showing thatsignal transducer and activator of tran-scription 3 (STAT3)- or STAT6-activatingcytokines yield predominantly IRE1-mediated cathepsin expression and secre-

tion suggests that UPR activation in TAMs contributes to cancer invasion(125). So far, very little has been described in gliomas except for therole of IRE1 in controlling the production of the proinflammatorychemokines, such as IL-6, IL-8, or CXCL3 (52, 102). Nonetheless,UPR activation may contribute to cancer progression by the reciprocalcommunication between the tumor and surrounding cells, and there-fore, targeting glioma stromal cells through UPR modulation maypose a promising treatment strategy.

ER Proteostasis Control and Response to Chemotherapy andRadiotherapy in GBMER proteostasis and current treatmentsModulating the protein folding capacity of the ER by interfering withprotein trafficking, synthesis, quality control, or degradation offers at-tractive strategies for developing new anticancer drugs. The currenttherapeutic and pharmacological strategies that target ER proteostasisin cancer focus either on exacerbating ER stress to a level with whichtumor cells cannot cope and therefore die or on decreasing the adapt-ive capacity of the tumor cells, leading to loss of selective advantageand tumor death. Over the past 5 years, several inhibitors of the threeUPR sensors have been developed (Table 1) (44, 58, 126–140). Somenew drugs are now tested to specifically target particular UPR sensorsto kill cancer cells or sensitize them to commonly used treatments. Todate, four compounds reportedly modulate ATF6 signaling. The pro-tein disulfide isomerase PDIA5 is critical for ATF6 activation, enablingits export from ER under stress conditions; genetic or pharmacologicalinhibition of the PDIA5/ATF6 axis (using the PDI inhibitor 16F16)sensitizes leukemia cells to imatinib treatment (58). Similarly, in a

Sirt1 PCAF

HDAC4

Ac

Nucleus

Promoters Histonemodifications

BMI1

MAcAc

M

PERK

AT

F3

ATF4XBP1s ATF6f

PCAFHDAC1

JMJD3

GCN5

SAGA

ATACMethyltransferases

CHOPATF3

CBX7

UPR targetgenesCHOPATF3JMJD3RTN-1C

EGR1GRP78

chaetocin

Fig. 3. Epigenetic regulation in ER stress signaling. Histone deacetylases (HDACs) and HAT-mediated regulationof ER stress signaling through chromatin remodeling in the nucleus and through posttranslational modification ofselect proteins in the cytosol. The pathways in black have been described in human brain tumors. CBX7, chromo-box 7; EGR1, early growth response 1; SIRT1, sirtuin 1.

6 of 18

Page 7: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

CREDIT:A.KITTE

RMAN/SCIENCESIGNALING

SC I ENCE S I GNAL ING | R EV I EW

on March 7, 2021

http://stke.sciencemag.org/

Dow

nloaded from

more recent work, it was demonstrated that ceapins, a class of pyrazoleamides, blocked ATF6 signaling in response to ER stress by trapping itin the ER (126, 127). On the other hand, Plate et al. identified two non-toxic small molecules, compounds 147 and 263, which selectively acti-vated the ATF6 branch of the UPR (128). They further demonstratethat those compounds reduced secretion and extracellular aggregationof destabilized amyloidogenic proteins (128). Both approaches, eitherblocking ATF6 activation or promoting it, may therefore represent use-ful strategies for controlling ER proteostasis in various human diseases,including cancers.

Most of the IRE1 modulators target the nucleotide-binding pocketto control IRE1 RNase activity. IRE1 RNase inhibitors from the sali-cylaldehyde family include 4m8C, ManKindCorp (MKC) analogs,3-methoxy-6-bromosalicylaldehyde, and STF-083010 (Table 1). 4m8Cbinds the catalytic site in IRE1 to block XBP1 cleavage and RIDD(141). 3-Methoxy-6-bromosalicylaldehyde also blocks XBP1 cleavageand subsequent RIDD in a reversible way (130). STF-083010 and MKC-3946 inhibit tumor growth in a mouse model of human multiple my-eloma (130, 131, 135). MKC-3946 also shows synergistic effects in

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

combination with the proteasome inhibitor bortezomib in multiple my-eloma (131). From screening of small molecules in an XBP1 splicingreporter system, toyocamycin was identified as a specific RNase inhib-itor and affected neither IRE1 phosphorylation nor the other UPR arms(142). Toyocamycin also shows synergistic effects with bortezomibin inducing multiple myeloma apoptosis (142). In the same screen,trierixin and quinotrierixin were also identified, although their mech-anisms of action were not elucidated (143, 144). Other IRE1 modula-tors interact with the adenosine triphosphate (ATP)–binding pocketto stabilize an active form of the kinase domain. The type I ATP-competitive broad kinase inhibitors sunitinib and APY29 activateIRE1 RNase activity in cultured insulinoma (INS-1) cells (145). Incontrast, the type II ATP kinase inhibitor compound 3 prevents thekinase activity, oligomerization, and RNase activity of IRE1 in INS-1 cells(136). Finally, ATP-competitive IRE1 kinase-inhibiting RNase at-tenuators (KIRAs), which allosterically inhibit IRE1 RNase activityby breaking oligomers, were recently discovered. KIRA6, an optimizedKIRA, inhibits IRE1 in mouse models and promotes cell survival un-der ER stress (134). Finally, IRE1-derived peptides modulate IRE1

†×†

†×††

XBP1s XBP1s

ATF6f

Tumor cell

Endothelial cell

Immune/inflammatory cell MacrophagesDendritic cellsT lymphocytes

Neutrophils

O2 nutrients

ATF4ATF4

VEGFAFGF2IL-6

VEGFAIL-6TNFα

IL-6IL-23TNFα

Cathepsin Tapasin

AKT

VEGFR1

VEGFA

Arginase 1

Nrf2

HIF1α

MMP2-7LAMP-3

ADAM17

Inflammation Immunesuppression

Invasion andmetastasis

Resistance togrowth suppressors

Deregulated cellularenergetics

Cell survival Angiogenesis

PERKPERKPERK

IRE1IRE1IRE1

ATF6ATF6ATF6

PERKPERKPERK

IRE1IRE1IRE1

ATF6ATF6ATF6

PERKPERKPERK

Fig. 4. UPR in the reciprocal communication between tumor and stromal cells. In tumor cells, activation of the UPR and its downstream effectors [ATF4, nuclearfactor (erythroid-derived 2)–like 2 (NRF2), XBP1s, and ATF6] triggers the transcriptional program contributing to cancer hallmarks, including invasion, metastasis, deregulationof cellular energetics, and sustained proliferation. In addition, the UPR modulates the tumor microenvironment by inducing the production of proinflammatory and proan-giogenic cytokines and chemokines. Once released, the latter shape tumor stromal cells to support cancer progression and resistance to treatment. Upon binding to VEGFreceptor 1 (VEGFR1) on endothelial cells, tumor-secreted VEGFA induces a UPR that supports endothelial cell survival, proliferation, and migration in an AKT-dependentmanner. In turn, new blood vessels are formed, providing the extensively growing tumor with oxygen and nutrient supplies. Other UPR-regulated secreted factors triggerthe UPR in tumor-infiltrating immune cells. As a consequence, those cells produce proinflammatory cytokines and lose their ability to cross-present antigens, thus enablingtumor escape from immune surveillance.

7 of 18

Page 8: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

SC I ENCE S I GNAL ING | R EV I EW

Table 1. Drugs targeting the UPR. Names, structures, and target of molecules identified to target directly the ATF6 (green), IRE1 (pink), or PERK (yellow)pathways. All the molecules indicated are inhibitors except for compounds 147 and 263 that activate ATF6.

Ob

Pathway

acz et al., Sci. Signal. 10, ea

Name

al2323 (2017) 14 March 2017

Structure

Target Reference

ATF6

16F16

PDI (58)

Ceapins

ATF6 (126, 127)

Compound 147

Dow

nl

Activators ofATF6

(128)

oa

Compound 263

ded fr

om on M

arch 7, 2021http://stke.sciencem

ag.org/

IRE1

4μ8c

IRE1 RNase (129)

MKC analogs

IRE1 RNase (130–133)

3-Ethoxy-5,6-dibromosalicylaldehyde

IRE1 RNase

(130)

KIRA6

IRE1 kinase (134)

STF-083010

IRE1 RNase (135)

Compound 3

IRE1 kinase (136)

continued on next page

8 of 18

Page 9: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

SC I ENCE S I GNAL ING | R EV I EW

on March 7, 2021

http://stke.sciencemag.org/

Dow

nloaded from

oligomeric status upon ER stress and uncouple XBP1 mRNA splicingfrom RIDD both in cultured HuH7 human hepatoma cells and inCaenorhabditis elegans (146). IRE1 inhibitors are suitable specificdrugs to kill cancer cells or sensitize them to common chemo- orradiotherapies.

PERK phosphorylation is inhibited by compound 38 (GSK2606414).This compound decreases pancreatic tumor growth in a mouse model(147). The related drug GSK2656157 is also efficient in vivo and reducescell metabolism and tumor-associated angiogenesis (44). Small mole-cules also attenuate PERK-dependent signaling by targeting down-stream eIF2a complexes. ISRIB reverses the effects mediated by eIF2aphosphorylation without directly affecting PERK phosphorylation (137)but rather inhibits the exchange factor eIF2B (148). Salubrinal blocks theprotein phosphatase 1 (PP1) in complex with either CreP or the growtharrest and DNA damage 34 (GADD34) proteins that dephosphorylateeIF2a either constitutively or under ER stress, respectively, leading to theretardation of mRNA translation (138). In contrast, guanabenz was de-scribed to inhibit only the PP1-GADD34 complex under conditionsof ER stress (139, 141). Prolonged eIF2a phosphorylation also leadsto increased expression of proapoptotic genes (141). A novel inhibitorof the PP1c-GADD34 pathway, Sephin, was recently discovered andwas shown to improve the condition of Charcot-Marie-Tooth diseasein mice (140). Thus, the discovery of multiple small molecules thattarget the UPR with positive outcomes in preclinical models of variousdiseases highlights the fact that UPR signaling modules are suitabletherapeutic targets; further work will reveal whether these drugs havepotential for treating brain cancer.

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

Induced imbalance in ER proteostasis in GBM as atherapeutic approachOver the past 20 years, the perturbation of ER homeostasis leading toan increased proteotoxic burden has been proposed as a novel strategyto kill cancer cells. As such, a large number (>55) of small mole-cules have been tested on GBM cell lines and induced cell death by amechanism that indirectly perturbs ER proteostasis, hence high-lighting their potential use as therapeutic agents (149, 150) [Table 2(22, 65–67, 151–211)]. The impact of these molecules on ER proteos-tasis imbalance was in most cases (85%) inferred by the up-regulationof GRP78 and/or CHOP mRNA or protein abundance, but generally,the causality of ER stress in the cell death process was not demon-strated. Currently, the standard treatment for GBM comprises surgicalresection of the tumor, followed by radiotherapy and exposure to thealkylating agent TMZ (212). As a stand-alone treatment, TMZ hasbeen shown to induce ER proteostasis imbalance in GBM cells, andits effects toward inducing cell death are potentiated by GRP78mRNAsilencing (22). Moreover, TMZ treatment of U87 cells (a GBM cellline) promotes the activation of the PERK pathway (213). To date,no clear link between TMZ and the IRE1 arm of the UPR is available,although several links between radiation therapy and the machinerycontrolling ER proteostasis have been established. The presence of asingle-nucleotide polymorphism (rs12435998) in suppressor of Lin-12–like protein 1 (SEL1L), an ERAD E3 ubiquitin ligase adaptor sub-unit, predicts better response of patients to radio-chemotherapy and isassociated with longer survival (214). Similarly, the ER-resident lectin-like chaperone calreticulin modulates radiosensitivity of the U251MG

Pathway

Name Structure Target Reference

PERK

GSK2656157

PERK (44)

ISRIB

eIF2β (137)

Salubrinal

GADD34 (PP1c) (138)

Guanabenz

GADD34 (PP1c) (139)

Sephin 1/IFB-088

GADD34 (PP1c) (140)

9 of 18

Page 10: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

SC I ENCE S I GNAL ING | R EV I EW

Table 2. UPR modulating drugs in GBM. Molecules used in GBM models and reported to act through the modulation of ER proteostasis. HSP72, heat shockprotein 72; Hsc70, heat shock cognate 70.

Ob

Model

acz et

al., Sci. Sign

Drug name

al. 10, eaal2323 (2017) 14 March 2017

Link to ER stress

Cellular impact Clinicaltrial

(yes/no)

R

eference

In vivo

Humancell lines

2,5-Dimethyl-celecoxib

GRP78 and CHOP induction Apoptosis induction No (151)

Δ9-Tetrahydrocannabinol A

TF4, CHOP, and TRB3 induction andeIF2α phosphorylation

Apoptosis induction, reducedtumor growth, and autophagy

Yes (

152, 153)

Asiatic acid (2,3,23-trihydroxy-12-ursen-28-oic acid, C30H48O5) c

GRP78 and calpain induction,alnexin and IRE1α down-regulation

Cell death induction

No (154)

Epigallocatechin 3-gallate + TMZ

GRP78 down-regulation Increased mice survival andincreased glioma cellsensitivity to TZM

No

(22, 155)

NEO212 (TMZ conjugated toperillyl alcohol)

CHOP induction

Cell death induction No (156)

D

Perillyl alcohol G RP78, ATF3, and CHOP induction

ow

Cytotoxicity and decreasedinvasion

Yes (

157, 158)

n

loa Piperlongumine

de

CHOP, eIF2a, ATF4, GADD34, andGRP78 induction

ROS-induced cell death

No (159)

d

fro In vitro Primaries RDC11

hm

GRP78 and CHOPinduction, andXBP1 splicing

DNA damage and apoptosisinduction, and cell growth

inhibition

No

(66)

tt

p:// TMZ + chloroquine CHOP induction

stk

Autophagy inhibition andapoptosis induction

No

(160)

e

.sc ienc

2-Amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}

acetamide (OSU-03012)

Involvement of GRP78 andPERK pathways

Cell death induction

No (161)

e

ma g Celecoxib + sildenafil

.o

eIF2α phosphorylation andactivation of ATF4/CHOP pathway

Autophagy and cell deathinduction

No

(162)

r

g/

o Terpyridineplatinum(II) complexes GRP78 induction P

n

erturbation of redox metabolismand cell cycle arrest

No

(163)

M

ar H ch

uman celllines

TMZ + SKI-II (4-((4-(4-chlorophenyl)-2-thiazolyl)amino)phenol)

GRP78 and CHOP induction

ROS-induced cell death No (164)

7

, 2 0 Withaferin A GRP78, IRE1, and CHOP induction

2

ROS production and apoptosisinduction

No

(165)

1

2-Deoxy-D-glucose

ER stress response gene signature IL-8 induction No (166)

2-Deoxy-D-glucose + cisplatin

GRP78 induction Autophagy inhibition No (167)

2-Hydroxyoleic acid

IRE1α, CHOP, and ATF4 induction,XBP1 splicing, and eIF2α

phosphorylation

Cell cycle arrest and autophagyinduction

No

(168)

5-Androstene 3β,17α diol (17α-AED)

GRP78 and CHOP induction, andactivation of PERK/eIF2α signaling

Autophagy induction

No (169)

Amiodarone + TRAIL

CHOP induction Apoptosis induction No (170)

Antp-TPR hybrid peptide

GRP78 and CHOP induction Cell death and cytotoxicityinduction

No

(171)

Berberine G

RP78, CHOP, and PERK induction,and eIF2α phosphorylation

Apoptosis induction and ROSgeneration

No (

172, 173)

Bufalin

GRP78 and CHOP induction, andPERK and eIF2α phosphorylation

Apoptosis and autophagyinduction

No

(174)

continued on next page

10 of 18

Page 11: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

SC I ENCE S I GNAL ING | R EV I EW

Ob

Model

acz et

al., Sci. Sign

Drug name

al. 10, eaal2323 (2017) 14 March 2017

Link to ER stress

Cellular impact Clinicaltrial

(yes/no)

R

eference

Candidaspongiolide (CAN)

Activation of PERK/eIF2α signaling Apoptosis induction and proteinsynthesis inhibition in normal cells

No

(175)

Celastol

HSP72 and HSP90 induction Autophagy induction andaccumulation of protein aggregates

No

(176)

Celecoxib + γ-irradiation

CHOP induction Cell cycle arrest and autophagyinduction under hypoxia

Yes

(177)

C

elecoxib/2,5-dimethyl-celecoxib + bortezomib GRP78 and CHOP induction Apoptosis induction No (65)

Copper (Cu)

GRP78 induction and aggregation ROS generation No (178)

Cyano enone of methyl boswellates

Activation of IRE1α and PERK Apoptosis induction No (179)

Fatsioside A

PERK and eIF2α phosphorylation,and CHOP induction

Apoptosis induction

No (180)

Fluoxetine A

ctivation of PERK/eIF2α/ATF4 andATF6/CHOP signaling

Apoptosis induction

No (181)

D

Glucosamine G RP78, IRE1α, and eIF2α induction Autophagic cell death induction No (182)

o

wn l Nelfinavir/atazanavir

oa

Induction of GRP78, CHOP, andPERK/eIF2α/ATF4 activation a

de

Cell death induction andccumulation of protein aggregates

(misfolding)

Yes

(22, 67)

d

fr om

Minocycline (7-dimethylamino-6-desoxytetracycline; Mino) a

h

PERK/eIF2α/CHOP and IRE1ctivation, XBP1 splicing, and GRP78

induction

Apoptosis and autophagyinduction

No

(184)

tt

p:// Phenethyl isothiocyanate

stk

GRP78, CHOP, XBP1, IRE1α, andcalpain 1 and 2 induction

e.

Apoptosis induction, decreasedmigration and invasion, and cell

cycle arrest

No (

185–187)

s

cie ncem

Polyether ionophore antibiotics(monensin, salinomycin, nigericin, narasin,

and lasalocid A)

CHOP and ATF4 induction, andeIF2a phosphorylation

TRAIL-mediated apoptosis

No (188)

a

g. org

Prenyl-phloroglucinol derivative[2,4-bis(4-fluorophenylacetyl)phloroglucinol]

o/

GRP78, GRP94, IRE1, and CHOPinduction, and eIF2αphosphorylation

ROS generation and apoptosisinduction

No

(189)

n

M arc

Quinine, quinacrine, mefloquine,and hydroxychloroquine

CHOP induction

Apoptosis induction No (190)

h

7 , S1 (BH3 mimetics)

20

GRP78 and CHOP induction, andIRE1 activation

Apoptosis and autophagyinduction

No

(191)

2

1 Schweinfurthin analogs eIF2α phosphorylation and GRP78induction

Inhibition of cancer growth andapoptosis induction

No

(192)

Sulindac sulfide

GRP78 induction Cell death induction No (193)

TMZ

CHOP induction No (22)

Unsaturated fatty acids + irradiation

GRP78 induction I ncreased radiosensitivity and celldeath induction

No

(194)

Zoledronic acid

IRE1 induction Apoptosis induction No (195)

O

ther celllines

Ursolic acid A

ctivation of PERK/eIF2α/CHOP andIRE1/JNK pathway

Apoptosis and autophagyinduction

No

(196)

Valproate

GRP78, GRP94, calreticulin, andCHOP induction

Inhibition of proliferation

No ( 197, 198)

Wogonin

GRP78 induction and eIF2αphosphorylation

ROS production and apoptosisinduction

No

(199)

Yessotoxin

eIF2α and PERK phosphorylation,and XBP1 splicing

Cell cycle arrest and proteinsynthesis inhibition

No

(200)

continued on next page

11 of 18

Page 12: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

SC I ENCE S I GNAL ING | R EV I EW

http://stke.sciencemag.

Dow

nloaded from

cell line (215). Collectively, these results indicate that ER proteostasismight be an important factor in GBM cells’ sensitivity to irradiation.The ATF6 arm of the UPR contributes to irradiation resistance inGBM cells (77). A more detailed and systematic analysis of the con-tribution of the three arms of the UPR in GBM progression is stillrequired. In conclusion, although data remain scarce, evidence suggestthat control of ER proteostasis and the UPR tumor cells and in thetumor stroma might play significant roles in the therapeutic responseof GBM patients. In this context, molecules that directly cause proteo-toxic stress or those that impair adaptive signaling from the ER mighttherefore represent interesting therapeutic avenues as adjuvants to thecurrent treatments.

on March 7, 2021

org/

Conclusions and PerspectivesOn the basis of the aforementioned evidence, it has become clear thatcontrol of ER proteostasis through the UPR is an essential player incancer in general and in GBM in particular. The role of the UPR inGBM has been mostly investigated using cultured cells and animal(mouse) models, but data from human GBM tumors remain scarceto confirm the relevance of this pathway in real patients. As previouslyshown for other cancers, such as TNBCs, in which the constitutiveactivation of one branch of the UPR, namely, the IRE1/XBP1 axis,confers selective advantage and aggressiveness to tumor cells (50), itmight be conceivable that GBM tumors (or a subset) exhibit increasedUPR activation that, in turn, correlates with tumor aggressiveness. Forinstance, preliminary analysis of publicly available transcriptomes(216) reveals that a subset of GBM tumors (between 15 and 20%)exhibits a signature resembling high IRE1 activity, and this signaturecorrelated with shorter survival of the patients. Similar observationsare available for a few types of cancer, and therefore, such hypothesiscould be tested systematically. The current treatments applied to GBMinduce ER proteostasis imbalance and thereby may ultimately contrib-ute to the selection of an adapted cell population that is resistant to theinitial treatment. Drugs inducing further ER stress (such as salinomycin)sensitize glioma cells to TMZ treatment through the down-regulationof MGMT, N-methylpurine DNA glycosylase (MPG), and RAD51,three gene products involved in DNA repair (217), indicating thatTMZ-mediated toxicity through the DNA damage pathway may in-

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

terfere with the ER stress response, although the precise underlyingmolecular mechanisms remain unclear. Another approach would beto classify cancer cells as showing a selective advantage on the basis ofhigh basal ER stress signaling activity, as previously shown in the caseof oncogene-induced cell transformation (218). In this context, tumorcells exhibiting high basal ER stress signaling activity could representgood targets for drugs that selectively impair UPR adaptive signaling(as described in Table 1), and hence, resistance to treatments (mostlikely caused by either high adaptive capacity or hormesis—adaptionthrough low-dose exposure) (219) observed in the cancer cells couldbe dampened through selective inhibition of the three arms of theUPR. We speculate that the use of IRE1 inhibitors or ATF6 activationinhibitors in GBMs may therefore affect tumor cell sensitivity to TMZand irradiation. To achieve such a goal, it becomes evident that thesystematic analysis of UPR activation in human tumors could be usedas a stratification tool and, as a consequence, could predict better re-sponsiveness of tumor cells to adjuvant therapies.

REFERENCES AND NOTES1. R. Stupp, W. P. Mason, M. J. van den Bent, M. Weller, B. Fisher, M. J. Taphoorn, K. Belanger,

A. A. Brandes, C. Marosi, U. Bogdahn, J. Curschmann, R. C. Janzer, S. K. Ludwin, T. Gorlia,A. Allgeier, D. Lacombe, J. G. Cairncross, E. Eisenhauer, R. O. Mirimanoff; European Organisationfor Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups and theNational Cancer Institute of Canada Clinical Trials Group, Radiotherapy plus concomitant andadjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).

2. J. Pallud, E. Audureau, G. Noel, R. Corns, E. Lechapt-Zalcman, J. Duntze, V. Pavlov,J. Guyotat, P. D. Hieu, P. J. Le Reste, T. Faillot, C.-F. Litre, N. Desse, A. Petit, E. Emery,J. Voirin, J. Peltier, F. Caire, J.-R. Vignes, J.-L. Barat, O. Langlois, E. Dezamis, E. Parraga,M. Zanello, E. Nader, M. Lefranc, L. Bauchet, B. Devaux, P. Menei, P. Metellus; Club deNeuro-Oncologie of the Société Française de Neurochirurgie, Long-term results ofcarmustine wafer implantation for newly diagnosed glioblastomas: A controlledpropensity-matched analysis of a French multicenter cohort. Neuro Oncol. 17,1609–1619 (2015).

3. K. Reddy, L. E. Gaspar, B. D. Kavanagh, A. Waziri, D. M. Damek, D. Ney, K. O. Lillehei,C. Chen, Prospective evaluation of health-related quality of life in patients withglioblastoma multiforme treated on a phase II trial of hypofractionated IMRT withtemozolomide. J. Neurooncol. 114, 111–116 (2013).

4. D. N. Louis, A. Perry, G. Reifenberger, A. von Deimling, D. Figarella-Branger,W. K. Cavenee, H. Ohgaki, O. D. Wiestler, P. Kleihues, D. W. Ellison, The 2016 WorldHealth Organization classification of tumors of the central nervous system: A summary.Acta Neuropathol. 131, 803–820 (2016).

Model

Drug name Link to ER stress Cellular impact Clinicaltrial

(yes/no)

R

eference

Carbamazepine

GRP78 induction Unknown No (201)

Cyclosporine A

IRE1α and PERK phosphorylation,and GRP78 and CHOP induction

Apoptosis and autophagyinduction

No (

202, 203)

Desipramine A

ctivation of PERK/eIF2α and ATF6signaling, and CHOP induction

Autophagy and apoptosisinduction

No (

204, 205)

Ethanol H

sc70, GRP78, and GRP94 induction Unknown No ( 206, 207)

Lead (Pb acetate)

Modulates GRP78 mRNA Unknown No ( 208, 209)

Mercury (HgCl2) In

creased GRP78 protein expression Oxidative stress modulation No (209)

Oleyl glucosaminide derivative

GRP78, CHOP, p8, and RAPM4induction

Cell death induction

No (210)

Sesquiterpene coumarin DAW22

GRP78 and CHOP induction, andPERK, ATF6, and IRE1 activation

Apoptosis induction

No (211)

12 of 18

Page 13: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

SC I ENCE S I GNAL ING | R EV I EW

on March 7, 2021

http://stke.sciencemag.org/

Dow

nloaded from

5. M. G. Filbin, M. L. Suva, Gliomas Genomics and Epigenomics: Arriving at the start andknowing it for the first time. Annu. Rev. Pathol. 11, 497–521 (2016).

6. M. Christmann, B. Verbeek, W. P. Roos, B. Kaina, O6-Methylguanine-DNAmethyltransferase (MGMT) in normal tissues and tumors: Enzyme activity, promotermethylation and immunohistochemistry. Biochim. Biophys. Acta 1816, 179–190 (2011).

7. M. G. Vander Heiden, L. C. Cantley, C. B. Thompson, Understanding the Warburg effect:The metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

8. D. Hanahan, R. A. Weinberg, Hallmarks of cancer: The next generation. Cell 144, 646–674(2011).

9. H. Gaillard, T. García-Muse, A. Aguilera, Replication stress and cancer. Nat. Rev. Cancer15, 276–289 (2015).

10. N. Dejeans, S. Manie, C. Hetz, F. Bard, T. Hupp, P. Agostinis, A. Samali, E. Chevet, Addictedto secrete—Novel concepts and targets in cancer therapy. Trends Mol. Med. 20, 242–250(2014).

11. G. Leprivier, B. Rotblat, D. Khan, E. Jan, P. H. Sorensen, Stress-mediated translationalcontrol in cancer cells. Biochim. Biophys. Acta 1849, 845–860 (2015).

12. T. Gutiérrez, T. Simmen, Endoplasmic reticulum chaperones and oxidoreductases:Critical regulators of tumor cell survival and immunorecognition. Front. Oncol. 4, 291(2014).

13. M. Boyce, J. Yuan, Cellular response to endoplasmic reticulum stress: A matter of life ordeath. Cell Death Differ. 13, 363–373 (2006).

14. M. Schröder, R. J. Kaufman, The mammalian unfolded protein response. Annu. Rev.Biochem. 74, 739–789 (2005).

15. A. Bertolotti, Y. Zhang, L. M. Hendershot, H. P. Harding, D. Ron, Dynamic interactionof BiP and ER stress transducers in the unfolded-protein response. Nat. Cell Biol. 2,326–332 (2000).

16. A. V. Korennykh, P. F. Egea, A. A. Korostelev, J. Finer-Moore, C. Zhang, K. M. Shokat,R. M. Stroud, P. Walter, The unfolded protein response signals through high-orderassembly of Ire1. Nature 457, 687–693 (2009).

17. D. Jiang, M. Niwa, A. C. Koong, Targeting the IRE1a–XBP1 branch of the unfoldedprotein response in human diseases. Semin. Cancer Biol. 33, 48–56 (2015).

18. M. Maurel, E. Chevet, J. Tavernier, S. Gerlo, Getting RIDD of RNA: IRE1 in cell fateregulation. Trends Biochem. Sci. 39, 245–254 (2014).

19. P. Walter, D. Ron, The unfolded protein response: From stress pathway to homeostaticregulation. Science 334, 1081–1086 (2011).

20. D. Ron, P. Walter, Signal integration in the endoplasmic reticulum unfolded proteinresponse. Nat. Rev. Mol. Cell Biol. 8, 519–529 (2007).

21. I. Tabas, D. Ron, Integrating the mechanisms of apoptosis induced by endoplasmicreticulum stress. Nat. Cell Biol. 13, 184–190 (2011).

22. P. Pyrko, A. H. Schönthal, F. M. Hofman, T. C. Chen, A. S. Lee, The unfolded proteinresponse regulator GRP78/BiP as a novel target for increasing chemosensitivity inmalignant gliomas. Cancer Res. 67, 9809–9816 (2007).

23. L. S. Hart, J. T. Cunningham, T. Datta, S. Dey, F. Tameire, S. L. Lehman, B. Qiu, H. Zhang,G. Cerniglia, M. Bi, Y. Li, Y. Gao, H. Liu, C. Li, A. Maity, A. T. Tikhonenko, A. E. Perl,A. Koong, S. Y. Fuchs, J. A. Diehl, I. G. Mills, D. Ruggero, C. Koumenis,ER stress–mediated autophagy promotes Myc-dependent transformation and tumorgrowth. J. Clin. Invest. 122, 4621–4634 (2012).

24. T. Bagratuni, P. Wu, D. Gonzalez de Castro, E. L. Davenport, N. J. Dickens, B. A. Walker,K. Boyd, D. C. Johnson, W. Gregory, G. J. Morgan, F. E. Davies, XBP1s levels areimplicated in the biology and outcome of myeloma mediating different clinicaloutcomes to thalidomide–based treatments. Blood 116, 250–253 (2010).

25. P. M. Fernandez, S. O. Tabbara, L. K. Jacobs, F. C. Manning, T. N. Tsangaris,A. M. Schwartz, K. A. Kennedy, S. R. Patierno, Overexpression of the glucose-regulatedstress gene GRP78 in malignant but not benign human breast lesions.Breast Cancer Res. Treat. 59, 15–26 (2000).

26. H. Uramoto, K. Sugio, T. Oyama, S. Nakata, K. Ono, T. Yoshimastu, M. Morita, K. Yasumoto,Expression of endoplasmic reticulum molecular chaperone Grp78 in human lung cancerand its clinical significance. Lung Cancer 49, 55–62 (2005).

27. M. Shuda, N. Kondoh, N. Imazeki, K. Tanaka, T. Okada, K. Mori, A. Hada, M. Arai,T. Wakatsuki, O. Matsubara, N. Yamamoto, M. Yamamoto, Activation of the ATF6,XBP1 and grp78 genes in human hepatocellular carcinoma: A possible involvement ofthe ER stress pathway in hepatocarcinogenesis. J. Hepatol. 38, 605–614 (2003).

28. X. Xing, M. Lai, Y. Wang, E. Xu, Q. Huang, Overexpression of glucose-regulated protein78 in colon cancer. Clin. Chim. Acta 364, 308–315 (2006).

29. F. Tameire, I. I. Verginadis, C. Koumenis, Cell intrinsic and extrinsic activators of theunfolded protein response in cancer: Mechanisms and targets for therapy. Semin.Cancer Biol. 33, 3–15 (2015).

30. Z. Niu, M. Wang, L. Zhou, L. Yao, Q. Liao, Y. Zhao, Elevated GRP78 expression isassociated with poor prognosis in patients with pancreatic cancer. Sci. Rep. 5, 16067(2015).

31. A. Mozos, G. Roué, A. Lopez-Guillermo, P. Jares, E. Campo, D. Colomer, A. Martinez,The expression of the endoplasmic reticulum stress sensor BiP/GRP78 predicts

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

response to chemotherapy and determines the efficacy of proteasome inhibitors indiffuse large b-cell lymphoma. Am. J. Pathol. 179, 2601–2610 (2011).

32. K. Matsuo, M. J. Gray, D. Y. Yang, S. A. Srivastava, P. B. Tripathi, L. A. Sonoda, E.-J. Yoo,L. Dubeau, A. S. Lee, Y. G. Lin, The endoplasmic reticulum stress marker, glucose-regulated protein-78 (GRP78) in visceral adipocytes predicts endometrial cancerprogression and patient survival. Gynecol. Oncol. 128, 552–559 (2013).

33. E. Dufey, H. Urra, C. Hetz, ER proteostasis addiction in cancer biology: Novel concepts.Semin. Cancer Biol. 33, 40–47 (2015).

34. H. Urra, E. Dufey, T. Avril, E. Chevet, C. Hetz, Endoplasmic reticulum stress and thehallmarks of cancer. Trends Cancer 2, 252–262 (2016).

35. J. Heijmans, J. F. van Lidth de Jeude, B.-K. Koo, S. L. Rosekrans, M. C. Wielenga,M. van de Wetering, M. Ferrante, A. S. Lee, J. J. M. Onderwater, J. C. Paton, A. W. Paton,A. M. Mommaas, L. L. Kodach, J. C. Hardwick, D. W. Hommes, H. Clevers, V. Muncan,G. R. van den Brink, ER stress causes rapid loss of intestinal epithelial stemness throughactivation of the unfolded protein response. Cell Rep. 3, 1128–1139 (2013).

36. N. Dejeans, K. Barroso, M. E. Fernandez-Zapico, A. Samali, E. Chevet, Novel roles of theunfolded protein response in the control of tumor development and aggressiveness.Semin. Cancer Biol. 33, 67–73 (2015).

37. E. Bobrovnikova-Marjon, C. Grigoriadou, D. Pytel, F. Zhang, J. Ye, C. Koumenis,D. Cavener, J. A. Diehl, PERK promotes cancer cell proliferation and tumor growth bylimiting oxidative DNA damage. Oncogene 29, 3881–3895 (2010).

38. A. Avivar-Valderas, E. Salas, E. Bobrovnikova-Marjon, J. A. Diehl, C. Nagi, J. Debnath,J. A. Aguirre-Ghiso, PERK integrates autophagy and oxidative stress responses topromote survival during extracellular matrix detachment. Mol. Cell. Biol. 31, 3616–3629(2011).

39. A. C. Ranganathan, L. Zhang, A. P. Adam, J. A. Aguirre-Ghiso, Functional coupling ofp38-induced up-regulation of BiP and activation of RNA-dependent protein kinase–likeendoplasmic reticulum kinase to drug resistance of dormant carcinoma cells.Cancer Res. 66, 1702–1711 (2006).

40. Y.-x. Feng, E. S. Sokol, C. A. Del Vecchio, S. Sanduja, J. H. L. Claessen, T. A. Proia, D. X. Jin,F. Reinhardt, H. L. Ploegh, Q. Wang, P. B. Gupta, Epithelial-to-mesenchymal transitionactivates PERK–eIF2a and sensitizes cells to endoplasmic reticulum stress. Cancer Discov.4, 702–715 (2014).

41. H. Mujcic, A. Nagelkerke, K. M. Rouschop, S. Chung, N. Chaudary, P. N. Span, B. Clarke,M. Milosevic, J. Sykes, R. P. Hill, M. Koritzinsky, B. G. Wouters, Hypoxic activation of thePERK/eIF2a arm of the unfolded protein response promotes metastasis throughinduction of LAMP3. Clin. Cancer Res. 19, 6126–6137 (2013).

42. H. Zhu, X. Chen, B. Chen, B. Chen, W. Song, D. Sun, Y. Zhao, Activating transcriptionfactor 4 promotes esophageal squamous cell carcinoma invasion and metastasis in miceand is associated with poor prognosis in human patients. PLOS ONE 9, e103882 (2014).

43. Y. Wang, G. N. Alam, Y. Ning, F. Visioli, Z. Dong, J. E. Nor, P. J. Polverini, The unfoldedprotein response induces the angiogenic switch in human tumor cells through thePERK/ATF4 pathway. Cancer Res. 72, 5396–5406 (2012).

44. C. Atkins, Q. Liu, E. Minthorn, S.-Y. Zhang, D. J. Figueroa, K. Moss, T. B. Stanley, B. Sanders,A. Goetz, N. Gaul, A. E. Choudhry, H. Alsaid, B. M. Jucker, J. M. Axten, R. Kumar,Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenicactivity. Cancer Res. 73, 1993–2002 (2013).

45. H.-Y. Jiang, S. A. Wek, B. C. McGrath, D. Scheuner, R. J. Kaufman, D. R. Cavener, R. C. Wek,Phosphorylation of the a subunit of eukaryotic initiation factor 2 is required foractivation of NF-kB in response to diverse cellular stresses. Mol. Cell. Biol. 23, 5651–5663(2003).

46. C. Greenman, P. Stephens, R. Smith, G. L. Dalgliesh, C. Hunter, G. Bignell, H. Davies,J. Teague, A. Butler, C. Stevens, S. Edkins, S. O’Meara, I. Vastrik, E. E. Schmidt, T. Avis,S. Barthorpe, G. Bhamra, G. Buck, B. Choudhury, J. Clements, J. Cole, E. Dicks, S. Forbes,K. Gray, K. Halliday, R. Harrison, K. Hills, J. Hinton, A. Jenkinson, D. Jones, A. Menzies,T. Mironenko, J. Perry, K. Raine, D. Richardson, R. Shepherd, A. Small, C. Tofts, J. Varian,T. Webb, S. West, S. Widaa, A. Yates, D. P. Cahill, D. N. Louis, P. Goldstraw, A. G. Nicholson,F. Brasseur, L. Looijenga, B. L. Weber, Y. E. Chiew, A. DeFazio, M. F. Greaves, A. R. Green,P. Campbell, E. Birney, D. F. Easton, G. Chenevix-Trench, M. H. Tan, S. K. Khoo, B. T. Teh,S. T. Yuen, S. Y. Leung, R. Wooster, P. A. Futreal, M. R. Stratton, Patterns of somatic mutationin human cancer genomes. Nature 446, 153–158 (2007).

47. Z. Xue, Y. He, K. Ye, Z. Gu, Y. Mao, L. Qi, A conserved structural determinant located atthe interdomain region of mammalian inositol-requiring enzyme 1a. J. Biol. Chem. 286,30859–30866 (2011).

48. H. Sun, D.-C. Lin, X. Guo, B. K. Masouleh, S. Gery, Q. Cao, S. Alkan, T. Ikezoe, C. Akiba,R. Paquette, W. Chien, C. Muller-Tidow, Y. Jing, K. Agelopoulos, M. Müschen,H. P. Koeffler, Inhibition of IRE1a-driven pro-survival pathways is a promisingtherapeutic application in acute myeloid leukemia. Oncotarget 7, 18736–18749 (2016).

49. L. Romero-Ramirez, H. Cao, D. Nelson, E. Hammond, A. H. Lee, H. Yoshida, K. Mori,L. H. Glimcher, N. C. Denko, A. J. Giaccia, Q.-T. Le, A. C. Koong, XBP1 is essential forsurvival under hypoxic conditions and is required for tumor growth. Cancer Res. 64,5943–5947 (2004).

13 of 18

Page 14: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

SC I ENCE S I GNAL ING | R EV I EW

on March 7, 2021

http://stke.sciencemag.org/

Dow

nloaded from

50. X. Chen, D. Iliopoulos, Q. Zhang, Q. Tang, M. B. Greenblatt, M. Hatziapostolou, E. Lim,W. L. Tam, M. Ni, Y. Chen, J. Mai, H. Shen, D. Z. Hu, S. Adoro, B. Hu, M. Song, C. Tan,M. D. Landis, M. Ferrari, S. J. Shin, M. Brown, J. C. Chang, X. S. Liu, L. H. Glimcher, XBP1promotes triple-negative breast cancer by controlling the HIF1a pathway. Nature 508,103–107 (2014).

51. K. J. Simpson, L. M. Selfors, J. Bui, A. Reynolds, D. Leake, A. Khvorova, J. S. Brugge,Identification of genes that regulate epithelial cell migration using an siRNA screeningapproach. Nat. Cell Biol. 10, 1027–1038 (2008).

52. G. Auf, A. Jabouille, S. Guerit, R. Pineau, M. Delugin, M. Bouchecareilh, N. Magnin,A. Favereaux, M. Maitre, T. Gaiser, A. von Deimling, M. Czabanka, P. Vajkoczy, E. Chevet,A. Bikfalvi, M. Moenner, Inositol-requiring enzyme 1a is a key regulator of angiogenesisand invasion in malignant glioma. Proc. Natl. Acad. Sci. U.S.A. 107, 15553–15558 (2010).

53. P. Hu, Z. Han, A. D. Couvillon, R. J. Kaufman, J. H. Exton, Autocrine tumor necrosis factoralpha links endoplasmic reticulum stress to the membrane death receptor pathwaythrough IRE1a-mediated NF-kB activation and down-regulation of TRAF2 expression.Mol. Cell. Biol. 26, 3071–3084 (2006).

54. E. R. Pereira, N. Liao, G. A. Neale, L. M. Hendershot, Transcriptional and post-transcriptional regulation of proangiogenic factors by the unfolded protein response.PLOS ONE 5, e12521 (2010).

55. B. Drogat, P. Auguste, D. T. Nguyen, M. Bouchecareilh, R. Pineau, J. Nalbantoglu,R. J. Kaufman, E. Chevet, A. Bikfalvi, M. Moenner, IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes toangiogenesis and tumor growth in vivo. Cancer Res. 67, 6700–6707 (2007).

56. D. M. Schewe, J. A. Aguirre-Ghiso, ATF6a-Rheb-mTOR signaling promotes survival ofdormant tumor cells in vivo. Proc. Natl. Acad. Sci. U.S.A. 105, 10519–10524 (2008).

57. M. Arai, N. Kondoh, N. Imazeki, A. Hada, K. Hatsuse, F. Kimura, O. Matsubara, K. Mori,T. Wakatsuki, M. Yamamoto, Transformation-associated gene regulation by ATF6aduring hepatocarcinogenesis. FEBS Lett. 580, 184–190 (2006).

58. A. Higa, S. Taouji, S. Lhomond, D. Jensen, M. E. Fernandez-Zapico, J. C. Simpson,J.-M. Pasquet, R. Schekman, E. Chevet, Endoplasmic reticulum stress-activatedtranscription factor ATF6a requires the disulfide isomerase PDIA5 to modulatechemoresistance. Mol. Cell. Biol. 34, 1839–1849 (2014).

59. E. Karali, S. Bellou, D. Stellas, A. Klinakis, C. Murphy, T. Fotsis, VEGF signals throughATF6 and PERK to promote endothelial cell survival and angiogenesis in the absence ofER stress. Mol. Cell 54, 559–572 (2014).

60. C. Druelle, C. Drullion, J. Desle, N. Martin, L. Saas, J. Cormenier, N. Malaquin, L. Huot,C. Slomianny, F. Bouali, C. Vercamer, D. Hot, A. Pourtier, E. Chevet, C. Abbadie, O. Pluquet,ATF6a regulates morphological changes associated with senescence in humanfibroblasts. Oncotarget 7, 67699–67715 (2016).

61. K. D. McCullough, J. L. Martindale, L.-O. Klotz, T.-Y. Aw, N. J. Holbrook, Gadd153sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbingthe cellular redox state. Mol. Cell. Biol. 21, 1249–1259 (2001).

62. S. Oyadomari, M. Mori, Roles of CHOP/GADD153 in endoplasmic reticulum stress.Cell Death Differ. 11, 381–389 (2004).

63. S. J. Marciniak, C. Y. Yun, S. Oyadomari, I. Novoa, Y. Zhang, R. Jungreis, K. Nagata,H. P. Harding, D. Ron, CHOP induces death by promoting protein synthesisand oxidation in the stressed endoplasmic reticulum. Genes Dev. 18, 3066–3077(2004).

64. M. Edagawa, J. Kawauchi, M. Hirata, H. Goshima, M. Inoue, T. Okamoto, A. Murakami,Y. Maehara, S. Kitajima, Role of activating transcription factor 3 (ATF3) in endoplasmicreticulum (ER) stress-induced sensitization of p53-deficient human colon cancer cells totumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosisthrough up-regulation of death receptor 5 (DR5) by zerumbone and celecoxib. J. Biol. Chem.289, 21544–21561 (2014).

65. A. Kardosh, E. B. Golden, P. Pyrko, J. Uddin, F. M. Hofman, T. C. Chen, S. G. Louie,N. A. Petasis, A. H. Schönthal, Aggravated endoplasmic reticulum stress as a basis forenhanced glioblastoma cell killing by bortezomib in combination with celecoxib or itsnon-coxib analogue, 2,5-dimethyl-celecoxib. Cancer Res. 68, 843–851 (2008).

66. X. Meng, M. L. Leyva, M. Jenny, I. Gross, S. Benosman, B. Fricker, S. Harlepp, P. Hebraud,A. Boos, P. Wlosik, P. Bischoff, C. Sirlin, M. Pfeffer, J.-P. Loeffler, C. Gaiddon,A ruthenium-containing organometallic compound reduces tumor growth throughinduction of the endoplasmic reticulum stress gene CHOP. Cancer Res. 69,5458–5466 (2009).

67. X. Tian, J. Ye, M. Alonso-Basanta, S. M. Hahn, C. Koumenis, J. F. Dorsey, Modulation ofCCAAT/enhancer binding protein homologous protein (CHOP)-dependent DR5expression by nelfinavir sensitizes glioblastoma multiforme cells to tumor necrosisfactor-related apoptosis-inducing ligand (TRAIL). J. Biol. Chem. 286, 29408–29416 (2011).

68. W. H. Kim, M. K. Jang, C. H. Kim, H. K. Shin, M. H. Jung, ATF3 inhibits PDX-1-stimulatedtransactivation. Biochem. Biophys. Res. Commun. 414, 681–687 (2011).

69. M. Endo, M. Mori, S. Akira, T. Gotoh, C/EBP homologous protein (CHOP) is crucial for theinduction of caspase-11 and the pathogenesis of lipopolysaccharide-inducedinflammation. J. Immunol. 176, 6245–6253 (2006).

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

70. G. Auf, A. Jabouille, M. Delugin, S. Guerit, R. Pineau, S. North, N. Platonova, M. Maitre,A. Favereaux, P. Vajkoczy, M. Seno, A. Bikfalvi, D. Minchenko, O. Minchenko, M. Moenner,High epiregulin expression in human U87 glioma cells relies on IRE1a and promotesautocrine growth through EGF receptor. BMC Cancer 13, 597 (2013).

71. A. Jabouille, M. Delugin, R. Pineau, A. Dubrac, F. Soulet, S. Lhomond, N. Pallares-Lupon,H. Prats, A. Bikfalvi, E. Chevet, C. Touriol, M. Moenner, Glioblastoma invasion andcooption depend on IRE1a endoribonuclease activity. Oncotarget 6, 24922–24934(2015).

72. N. Dejeans, O. Pluquet, S. Lhomond, F. Grise, M. Bouchecareilh, A. Juin,M. Meynard-Cadars, A. Bidaud-Meynard, C. Gentil, V. Moreau, F. Saltel, E. Chevet,Autocrine control of glioma cells adhesion and migration through IRE1a-mediatedcleavage of SPARC mRNA. J. Cell Sci. 125, 4278–4287 (2012).

73. S. B. Cullinan, D. Zhang, M. Hannink, E. Arvisais, R. J. Kaufman, J. A. Diehl, Nrf2 is a directPERK substrate and effector of PERK-dependent cell survival. Mol. Cell. Biol. 23,7198–7209 (2003).

74. A. Yacoub, H. A. Hamed, J. Allegood, C. Mitchell, S. Spiegel, M. S. Lesniak, B. Ogretmen,R. Dash, D. Sarkar, W. C. Broaddus, S. Grant, D. T. Curiel, P. B. Fisher, P. Dent, PERK–dependent regulation of ceramide synthase 6 and thioredoxin play a key role in mda-7/IL–24-induced killing of primary human glioblastoma multiforme cells. Cancer Res. 70,1120–1129 (2010).

75. T. Rzymski, A. Petry, D. Kračun, F. Rieß, L. Pike, A. L. Harris, A. Görlach, The unfoldedprotein response controls induction and activation of ADAM17/TACE by severe hypoxiaand ER stress. Oncogene 31, 3621–3634 (2012).

76. S. Jamison, Y. Lin, W. Lin, Pancreatic endoplasmic reticulum kinase activation promotesmedulloblastoma cell migration and invasion through induction of vascular endothelialgrowth factor A. PLOS ONE 10, e0120252 (2015).

77. D. Y. A. Dadey, V. Kapoor, A. Khudanyan, F. Urano, A. H. Kim, D. Thotala, D. E. Hallahan,The ATF6 pathway of the ER stress response contributes to enhanced viability inglioblastoma. Oncotarget 7, 2080–2092 (2016).

78. C. M. Toledo, Y. Ding, P. Hoellerbauer, R. J. Davis, R. Basom, E. J. Girard, E. Lee, P. Corrin,T. Hart, H. Bolouri, J. Davison, Q. Zhang, J. Hardcastle, B. J. Aronow, C. L. Plaisier,N. S. Baliga, J. Moffat, Q. Lin, X. N. Li, D.-H. Nam, J. Lee, S. M. Pollard, J. Zhu,J. J. Delrow, B. E. Clurman, J. M. Olson, P. J. Paddison, Genome-wide CRISPR-Cas9screens reveal loss of redundancy between PKMYT1 and WEE1 in Glioblastomastem-like cells. Cell Rep. 13, 2425–2439 (2015).

79. J. Shan, L. Fu, M. N. Balasubramanian, T. Anthony, M. S. Kilberg, ATF4-dependentregulation of the JMJD3 gene during amino acid deprivation can be rescued in ATF4-deficient cells by inhibition of deacetylation. J. Biol. Chem. 287, 36393–36403 (2012).

80. X. Liu, S. Guo, X. Liu, L. Su, Chaetocin induces endoplasmic reticulum stress responseand leads to death receptor 5-dependent apoptosis in human non-small cell lungcancer cells. Apoptosis 20, 1499–1507 (2015).

81. S.-H. Park, J. Kim, K. H. Do, J. Park, C. G. Oh, H. J. Choi, B. G. Song, S. J. Lee, Y. S. Kim,Y. Moon, Activating transcription factor 3-mediated chemo-intervention with cancerchemokines in a noncanonical pathway under endoplasmic reticulum stress. J. Biol.Chem. 289, 27118–27133 (2014).

82. P. Zhang, Q. Sun, C. Zhao, S. Ling, Q. Li, Y.-Z. Chang, Y. Li, HDAC4 protects cellsfrom ER stress induced apoptosis through interaction with ATF4. Cell. Signal. 26,556–563 (2014).

83. P. Baumeister, D. Dong, Y. Fu, A. S. Lee, Transcriptional induction of GRP78/BiP byhistone deacetylase inhibitors and resistance to histone deacetylase inhibitor–inducedapoptosis. Mol. Cancer Ther. 8, 1086–1094 (2009).

84. F.-M. Wang, Y.-J. Chen, H.-J. Ouyang, Regulation of unfolded protein responsemodulator XBP1s by acetylation and deacetylation. Biochem. J. 433, 245–252 (2011).

85. Z. Nagy, A. Riss, C. Romier, X. le Guezennec, A. R. Dongre, M. Orpinell, J. Han,H. Stunnenberg, L. Tora, The human SPT20-containing SAGA complex plays a direct rolein the regulation of endoplasmic reticulum stress-induced genes. Mol. Cell. Biol. 29,1649–1660 (2009).

86. D. Sela, L. Chen, S. Martin-Brown, M. P. Washburn, L. Florens, J. W. Conaway,R. C. Conaway, Endoplasmic reticulum stress-responsive transcription factor ATF6adirects recruitment of the Mediator of RNA polymerase II transcription and multiplehistone acetyltransferase complexes. J. Biol. Chem. 287, 23035–23045 (2012).

87. D. Sela, J. J. Conkright, L. Chen, J. Gilmore, M. P. Washburn, L. Florens, R. C. Conaway,J. W. Conaway, Role for human mediator subunit MED25 in recruitment of mediator topromoters by endoplasmic reticulum stress-responsive transcription factor ATF6a.J. Biol. Chem. 288, 26179–26187 (2013).

88. A. W. Schram, R. Baas, P. W. T. C. Jansen, A. Riss, L. Tora, M. Vermeulen, H. T. M. Timmers,A dual role for SAGA-associated factor 29 (SGF29) in ER stress survival by coordinationof both histone H3 acetylation and histone H3 lysine-4 trimethylation. PLOS ONE 8,e70035 (2013).

89. Q. J. Lew, K. L. Chu, J. Lee, P. L. Koh, V. Rajasegaran, J. Y. Teo, S.-H. Chao, PCAF interactswith XBP-1S and mediates XBP-1S-dependent transcription. Nucleic Acids Res. 39,429–439 (2011).

14 of 18

Page 15: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

SC I ENCE S I GNAL ING | R EV I EW

on March 7, 2021

http://stke.sciencemag.org/

Dow

nloaded from

90. Q. J. Lew, K. L. Chu, Y. L. Chia, B. Soo, J. P. Ho, C. H. Ng, H. S. Kwok, C.-M. Chiang, Y. Chang,S.-H. Chao, GCN5 inhibits XBP-1S-mediated transcription by antagonizing PCAF action.Oncotarget 6, 271–287 (2015).

91. I. Lassot, E. Estrabaud, S. Emiliani, M. Benkirane, R. Benarous, F. Margottin-Goguet, p300modulates ATF4 stability and transcriptional activity independently of itsacetyltransferase domain. J. Biol. Chem. 280, 41537–41545 (2005).

92. F. Di Sano, B. Fazi, R. Tufi, R. Nardacci, M. Piacentini, Reticulon-1C acts as a molecularswitch between endoplasmic reticulum stress and genotoxic cell death pathway inhuman neuroblastoma cells. J. Neurochem. 102, 345–353 (2007).

93. B. Fazi, S. Melino, S. De Rubeis, C. Bagni, M. Paci, M. Piacentini, F. Di Sano, Acetylation ofRTN-1C regulates the induction of ER stress by the inhibition of HDAC activity inneuroectodermal tumors. Oncogene 28, 3814–3824 (2009).

94. G. Gargiulo, M. Cesaroni, M. Serresi, N. de Vries, D. Hulsman, S. W. Bruggeman, C. Lancini,M. van Lohuizen, In vivo RNAi screen for BMI1 targets identifies TGF-b/BMP-ER stresspathways as key regulators of neural- and malignant glioma-stem cell homeostasis.Cancer Cell 23, 660–676 (2013).

95. M. Maurel, E. Chevet, Endoplasmic reticulum stress signaling: The microRNA connection.Am. J. Physiol. Cell Physiol. 304, C1117–C1126 (2013).

96. J.-P. Upton, L. Wang, D. Han, E. S. Wang, N. E. Huskey, L. Lim, M. Truitt, M. T. McManus,D. Ruggero, A. Goga, F. R. Papa, S. A. Oakes, IRE1a cleaves select microRNAs duringER stress to derepress translation of proapoptotic Caspase-2. Science 338, 818–822(2012).

97. E. Chevet, C. Hetz, A. Samali, Endoplasmic reticulum stress–activated cellreprogramming in oncogenesis. Cancer Discov. 5, 586–597 (2015).

98. T. Tokudome, A. Sasaki, M. Tsuji, Y. Udaka, H. Oyamada, H. Tsuchiya, K. Oguchi, ReducedPTEN expression and overexpression of miR-17-5p, -19a-3p, -19b-3p, -21-5p, -130b-3p,-221-3p and -222-3p by glioblastoma stem-like cells following irradiation. Oncol. Lett.10, 2269–2272 (2015).

99. Y. Li, F. Guessous, Y. Zhang, C. Dipierro, B. Kefas, E. Johnson, L. Marcinkiewicz, J. Jiang,Y. Yang, T. D. Schmittgen, B. Lopes, D. Schiff, B. Purow, R. Abounader, MicroRNA-34ainhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res. 69,7569–7576 (2009).

100. Z. Yan, J. Wang, C. Wang, Y. Jiao, W. Qi, S. Che, miR-96/HBP1/Wnt/b-catenin regulatorycircuitry promotes glioma growth. FEBS Lett. 588, 3038–3046 (2014).

101. J. Hollien, J. S. Weissman, Decay of endoplasmic reticulum-localized mRNAs during theunfolded protein response. Science 313, 104–107 (2006).

102. O. Pluquet, N. Dejeans, M. Bouchecareilh, S. Lhomond, R. Pineau, A. Higa, M. Delugin,C. Combe, S. Loriot, G. Cubel, N. Dugot-Senant, A. Vital, H. Loiseau, S. J. Gosline, S. Taouji,M. Hallett, J. N. Sarkaria, K. Anderson, W. Wu, F. J. Rodriguez, J. Rosenbaum, F. Saltel,M. E. Fernandez-Zapico, E. Chevet, Posttranscriptional regulation of PER1 underlies theoncogenic function of IREa. Cancer Res. 73, 4732–4743 (2013).

103. C. Hetz, E. Chevet, S. A. Oakes, Proteostasis control by the unfolded protein response.Nat. Cell Biol. 17, 829–838 (2015).

104. S. F. Hussain, D. Yang, D. Suki, K. Aldape, E. Grimm, A. B. Heimberger, The role of humanglioma-infiltrating microglia/macrophages in mediating antitumor immune responses.Neuro Oncol. 8, 261–279 (2006).

105. C. Charalambous, T. C. Chen, F. M. Hofman, Characteristics of tumor-associatedendothelial cells derived from glioblastoma multiforme. Neurosurg. Focus 20, E22 (2006).

106. B. Badie, J. M. Schartner, Flow cytometric characterization of tumor-associatedmacrophages in experimental gliomas. Neurosurgery 46, 957–961 (2000).

107. Y. Komohara, K. Ohnishi, J. Kuratsu, M. Takeya, Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J. Pathol. 216,15–24 (2008).

108. L. Bingle, N. J. Brown, C. E. Lewis, The role of tumour-associated macrophages in tumourprogression: Implications for new anticancer therapies. J. Pathol. 196, 254–265 (2002).

109. J. Wei, K. Gabrusiewicz, A. Heimberger, The controversial role of microglia in malignantgliomas. Clin. Dev. Immunol. 2013, 285246 (2013).

110. P. Allavena, A. Mantovani, Immunology in the clinic review series; focus on cancer:Tumour-associated macrophages: Undisputed stars of the inflammatory tumourmicroenvironment. Clin. Exp. Immunol. 167, 195–205 (2012).

111. A. Mantovani, S. Sozzani, M. Locati, P. Allavena, A. Sica, Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes.Trends Immunol. 23, 549–555 (2002).

112. M. R. Galdiero, C. Garlanda, S. Jaillon, G. Marone, A. Mantovani, Tumor associatedmacrophages and neutrophils in tumor progression. J. Cell. Physiol. 228, 1404–1412 (2013).

113. D. Hambardzumyan, D. H. Gutmann, H. Kettenmann, The role of microglia andmacrophages in glioma maintenance and progression. Nat. Neurosci. 19, 20–27 (2016).

114. F. Martinon, X. Chen, A.-H. Lee, L. H. Glimcher, TLR activation of the transcription factorXBP1 regulates innate immune responses in macrophages. Nat. Immunol. 11, 411–418(2010).

115. L. Chen, S. Jarujaron, X. Wu, L. Sun, W. Zha, G. Liang, X. Wang, E. C. Gurley, E. J. Studer,P. B. Hylemon, W. M. Pandak Jr., L. Zhang, G. Wang, X. Li, P. Dent, H. Zhou, HIV protease

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

inhibitor lopinavir-induced TNF-a and IL-6 expression is coupled to the unfoldedprotein response and ERK signaling pathways in macrophages. Biochem. Pharmacol. 78,70–77 (2009).

116. J. C. Goodall, C. Wu, Y. Zhang, L. McNeill, L. Ellis, V. Saudek, J. S. Gaston, Endoplasmicreticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23expression. Proc. Natl. Acad. Sci. U.S.A. 107, 17698–17703 (2010).

117. C. Morales, S. Rachidi, F. Hong, S. Sun, X. Ouyang, C. Wallace, Y. Zhang, E. Garret-Mayer,J. Wu, B. Liu, Z. Li, Immune chaperone gp96 drives the contributions of macrophages toinflammatory colon tumorigenesis. Cancer Res. 74, 446–459 (2014).

118. N. R. Mahadevan, J. Rodvold, H. Sepulveda, S. Rossi, A. F. Drew, M. Zanetti, Transmissionof endoplasmic reticulum stress and pro-inflammation from tumor cells to myeloid cells.Proc. Natl. Acad. Sci. U.S.A. 108, 6561–6566 (2011).

119. N. R. Mahadevan, V. Anufreichik, J. J. Rodvold, K. T. Chiu, H. Sepulveda, M. Zanetti, Cell-extrinsic effects of tumor ER stress imprint myeloid dendritic cells and impair CD8+ T cellpriming. PLOS ONE 7, e51845 (2012).

120. M. C. Wheeler, M. Rizzi, R. Sasik, G. Almanza, G. Hardiman, M. Zanetti, KDEL-retainedantigen in B lymphocytes induces a proinflammatory response: A possible role forendoplasmic reticulum stress in adaptive T cell immunity. J. Immunol. 181, 256–264(2008).

121. D. P. Granados, P.-L. Tanguay, M.-P. Hardy, É. Caron, D. de Verteuil, S. Meloche,C. Perreault, ER stress affects processing of MHC class I-associated peptides. BMCImmunol. 10, 10 (2009).

122. L. A. Norian, P. C. Rodriguez, L. A. O’Mara, J. Zabaleta, A. C. Ochoa, M. Cella, P. M. Allen,Tumor-infiltrating regulatory dendritic cells inhibit CD8+ T cell function via L-argininemetabolism. Cancer Res. 69, 3086–3094 (2009).

123. F. Osorio, S. J. Tavernier, E. Hoffmann, Y. Saeys, L. Martens, J. Vetters, I. Delrue,R. De Rycke, E. Parthoens, P. Pouliot, T. Iwawaki, S. Janssens, B. N. Lambrecht, Theunfolded-protein-response sensor IRE-1a regulates the function of CD8a+ dendriticcells. Nat. Immunol. 15, 248–257 (2014).

124. N. N. Iwakoshi, M. Pypaert, L. H. Glimcher, The transcription factor XBP-1 is essentialfor the development and survival of dendritic cells. J. Exp. Med. 204, 2267–2275(2007).

125. D. Yan, H.-W. Wang, R. L. Bowman, J. A. Joyce, STAT3 and STAT6 signaling pathwayssynergize to promote cathepsin secretion from macrophages via IRE1a activation.Cell Rep. 16, 2914–2927 (2016).

126. C. M. Gallagher, P. Walter, Ceapins inhibit ATF6a signaling by selectively preventingtransport of ATF6a to the Golgi apparatus during ER stress. eLife 5, e11880 (2016).

127. C. M. Gallagher, C. Garri, E. L. Cain, K. K. Ang, C. G. Wilson, S. Chen, B. R. Hearn,P. Jaishankar, A. Aranda-Diaz, M. R. Arkin, A. R. Renslo, P. Walter, Ceapins are a new classof unfolded protein response inhibitors, selectively targeting the ATF6a branch. eLife 5,e11878 (2016).

128. L. Plate, C. B. Cooley, J. J. Chen, R. J. Paxman, C. M. Gallagher, F. Madoux, J. C. Genereux,W. Dobbs, D. Garza, T. P. Spicer, L. Scampavia, S. J. Brown, H. Rosen, E. T. Powers,P. Walter, P. Hodder, R. L. Wiseman, J. W. Kelly, Small molecule proteostasis regulatorsthat reprogram the ER to reduce extracellular protein aggregation. eLife 5, e15550(2016).

129. B. C. Cross, P. J. Bond, P. G. Sadowski, B. K. Jha, J. Zak, J. M. Goodman, R. H. Silverman,T. A. Neubert, I. R. Baxendale, D. Ron, H. P. Harding, The molecular basis for selectiveinhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc. Natl.Acad. Sci. U.S.A. 109, E869–E878 (2012).

130. K. Volkmann, J. L. Lucas, D. Vuga, X. Wang, D. Brumm, C. Stiles, D. Kriebel,A. Der-Sarkissian, K. Krishnan, C. Schweitzer, Z. Liu, U. M. Malyankar, D. Chiovitti,M. Canny, D. Durocher, F. Sicheri, J. B. Patterson, Potent and selective inhibitorsof the inositol-requiring enzyme 1 endoribonuclease. J. Biol. Chem. 286,12743–12755 (2011).

131. N. Mimura, M. Fulciniti, G. Gorgun, Y.-T. Tai, D. Cirstea, L. Santo, Y. Hu, C. Fabre, J. Minami,H. Ohguchi, T. Kiziltepe, H. Ikeda, Y. Kawano, M. French, M. Blumenthal, V. Tam,N. L. Kertesz, U. M. Malyankar, M. Hokenson, T. Pham, Q. Zeng, J. B. Patterson,P. G. Richardson, N. C. Munshi, K. C. Anderson, Blockade of XBP1 splicing by inhibition ofIRE1a is a promising therapeutic option in multiple myeloma. Blood 119, 5772–5781(2012).

132. M. Sanches, N. M. Duffy, M. Talukdar, N. Thevakumaran, D. Chiovitti, M. D. Canny,K. Lee, I. Kurinov, D. Uehling, R. Al-awar, G. Poda, M. Prakesch, B. Wilson, V. Tam,C. Schweitzer, A. Toro, J. L. Lucas, D. Vuga, L. Lehmann, D. Durocher, Q. Zeng,J. B. Patterson, F. Sicheri, Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors. Nat. Commun. 5, 4202(2014).

133. S. Lhomond, N. Pallares, K. Barroso, K. Schmit, N. Dejeans, H. Fazli, S. Taouji,J. B. Patterson, E. Chevet, Adaptation of the secretory pathway in cancer through IRE1signaling. Methods Mol. Biol. 1292, 177–194 (2015).

134. R. Ghosh, L. Wang, E. S. Wang, B. G. Perera, A. Igbaria, S. Morita, K. Prado, M. Thamsen,D. Caswell, H. Macias, K. F. Weiberth, M. J. Gliedt, M. V. Alavi, S. B. Hari, A. K. Mitra,

15 of 18

Page 16: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

SC I ENCE S I GNAL ING | R EV I EW

on March 7, 2021

http://stke.sciencemag.org/

Dow

nloaded from

B. Bhhatarai, S. C. Schurer, E. L. Snapp, D. B. Gould, M. S. German, B. J. Backes, D. J. Maly,S. A. Oakes, F. R. Papa, Allosteric inhibition of the IRE1a RNase preserves cell viability andfunction during endoplasmic reticulum stress. Cell 158, 534–548 (2014).

135. I. Papandreou, N. C. Denko, M. Olson, H. Van Melckebeke, S. Lust, A. Tam,D. E. Solow-Cordero, D. M. Bouley, F. Offner, M. Niwa, A. C. Koong, Identification of anIre1a endonuclease specific inhibitor with cytotoxic activity against human multiplemyeloma. Blood 117, 1311–1314 (2011).

136. L. Wang, B. G. Perera, S. B. Hari, B. Bhhatarai, B. J. Backes, M. A. Seeliger, S. C. Schurer,S. A. Oakes, F. R. Papa, D. J. Maly, Divergent allosteric control of the IRE1aendoribonuclease using kinase inhibitors. Nat. Chem. Biol. 8, 982–989 (2012).

137. C. Sidrauski, D. Acosta-Alvear, A. Khoutorsky, P. Vedantham, B. R. Hearn, H. Li,K. Gamache, C. M. Gallagher, K. K. Ang, C. Wilson, V. Okreglak, A. Ashkenazi, B. Hann,K. Nader, M. R. Arkin, A. R. Renslo, N. Sonenberg, P. Walter, Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife 2, e00498 (2013).

138. M. Boyce, K. F. Bryant, C. Jousse, K. Long, H. P. Harding, D. Scheuner, R. J. Kaufman,D. Ma, D. M. Coen, D. Ron, J. Yuan, A selective inhibitor of eIF2a dephosphorylationprotects cells from ER stress. Science 307, 935–939 (2005).

139. P. Tsaytler, H. P. Harding, D. Ron, A. Bertolotti, Selective inhibition of a regulatory subunitof protein phosphatase 1 restores proteostasis. Science 332, 91–94 (2011).

140. I. Das, A. Krzyzosiak, K. Schneider, L. Wrabetz, M. D’Antonio, N. Barry, A. Sigurdardottir,A. Bertolotti, Preventing proteostasis diseases by selective inhibition of a phosphataseregulatory subunit. Science 348, 239–242 (2015).

141. C. Hetz, E. Chevet, H. P. Harding, Targeting the unfolded protein response in disease.Nat. Rev. Drug Discov. 12, 703–719 (2013).

142. M. Ri, E. Tashiro, D. Oikawa, S. Shinjo, M. Tokuda, Y. Yokouchi, T. Narita, A. Masaki, A. Ito,J. Ding, S. Kusumoto, T. Ishida, H. Komatsu, Y. Shiotsu, R. Ueda, T. Iwawaki, M. Imoto,S. Iida, Identification of Toyocamycin, an agent cytotoxic for multiple myelomacells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing. Blood Cancer J.2, e79 (2012).

143. T. Kawamura, E. Tashiro, K. Yamamoto, K. Shindo, M. Imoto, SAR study of a novel triene-ansamycin group compound, quinotrierixin, and related compounds, as inhibitors ofER stress-induced XBP1 activation. J. Antibiot. 61, 303–311 (2008).

144. Y. Futamura, E. Tashiro, N. Hironiwa, J. Kohno, M. Nishio, K. Shindo, M. Imoto, Trierixin,a novel Inhibitor of ER stress-induced XBP1 activation from Streptomyces sp. II. structureelucidation. J. Antibiot. 60, 582–585 (2007).

145. M. M. U. Ali, T. Bagratuni, E. L. Davenport, P. R. Nowak, M. C. Silva-Santisteban,A. Hardcastle, C. McAndrews, M. G. Rowlands, G. J. Morgan, W. Aherne, I. Collins,F. E. Davies, L. H. Pearl, Structure of the Ire1 autophosphorylation complex andimplications for the unfolded protein response. EMBO J. 30, 894–905 (2011).

146. M. Bouchecareilh, A. Higa, S. Fribourg, M. Moenner, E. Chevet, Peptides derived fromthe bifunctional kinase/RNase enzyme IRE1a modulate IRE1a activity and protect cellsfrom endoplasmic reticulum stress. FASEB J. 25, 3115–3129 (2011).

147. J. M. Axten, J. R. Medina, Y. Feng, A. Shu, S. P. Romeril, S. W. Grant, W. H. Li,D. A. Heerding, E. Minthorn, T. Mencken, C. Atkins, Q. Liu, S. Rabindran, R. Kumar,X. Hong, A. Goetz, T. Stanley, J. D. Taylor, S. D. Sigethy, G. H. Tomberlin, A. M. Hassell,K. M. Kahler, L. M. Shewchuk, R. T. Gampe, Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinaseR (PKR)-like endoplasmic reticulum kinase (PERK). J. Med. Chem. 55, 7193–7207(2012).

148. C. Sidrauski, J. C. Tsai, M. Kampmann, B. R. Hearn, P. Vedantham, P. Jaishankar,M. Sokabe, A. S. Mendez, B. W. Newton, E. L. Tang, E. Verschueren, J. R. Johnson,N. J. Krogan, C. S. Fraser, J. S. Weissman, A. R. Renslo, P. Walter, Pharmacologicaldimerization and activation of the exchange factor eIF2B antagonizes the integratedstress response. Elife 4, e07314 (2015).

149. P. J. Le Reste, T. Avril, V. Quillien, X. Morandi, E. Chevet, Signaling the unfolded proteinresponse in primary brain cancers. Brain Res. 1642, 59–69 (2016).

150. N. M. Peñaranda Fajardo, C. Meijer, F. A. E. Kruyt, The endoplasmic reticulum stress/unfolded protein response in gliomagenesis, tumor progression and as a therapeutictarget in glioblastoma. Biochem. Pharmacol. 118, 1–8 (2016).

151. J. J. Virrey, Z. Liu, H.-Y. Cho, A. Kardosh, E. B. Golden, S. G. Louie, K. J. Gaffney,N. A. Petasis, A. H. Schönthal, T. C. Chen, F. M. Hofman, Antiangiogenic activities of2,5-dimethyl-celecoxib on the tumor vasculature. Mol. Cancer Ther. 9, 631–641 (2010).

152. M. Salazar, A. Carracedo, I. J. Salanueva, S. Hernández-Tiedra, M. Lorente, A. Egia,P. Vazquez, C. Blázquez, S. Torres, S. Garcia, J. Nowak, G. M. Fimia, M. Piacentini,F. Cecconi, P. P. Pandolfi, L. González-Feria, J. L. Iovanna, M. Guzman, P. Boya, G. Velasco,Cannabinoid action induces autophagy-mediated cell death through stimulationof ER stress in human glioma cells. J. Clin. Invest. 119, 1359–1372 (2009).

153. M. Guzmán, M. J. Duarte, C. Blázquez, J. Ravina, M. C. Rosa, I. Galve-Roperh,C. Sánchez, G. Velasco, L. González-Feria, A pilot clinical study of D9-tetrahydrocannabinolin patients with recurrent glioblastoma multiforme. Br. J. Cancer 95, 197–203(2006).

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

154. C. V. Kavitha, A. K. Jain, C. Agarwal, A. Pierce, A. Keating, K. M. Huber, N. J. Serkova,M. F. Wempe, R. Agarwal, G. Deep, Asiatic acid induces endoplasmic reticulum stressand apoptotic death in glioblastoma multiforme cells both in vitro and in vivo.Mol. Carcinog. 54, 1417–1429 (2015).

155. T. C. Chen, W. Wang, E. B. Golden, S. Thomas, W. Sivakumar, F. M. Hofman, S. G. Louie,A. H. Schönthal, Green tea epigallocatechin gallate enhances therapeutic efficacy oftemozolomide in orthotopic mouse glioblastoma models. Cancer Lett. 302, 100–108(2011).

156. H.-Y. Cho, W. Wang, N. Jhaveri, D. J. Lee, N. Sharma, L. Dubeau, A. H. Schönthal,F. M. Hofman, T. C. Chen, NEO212, temozolomide conjugated to perillyl alcohol, is anovel drug for effective treatment of a broad range of temozolomide-resistant gliomas.Mol. Cancer Ther. 13, 2004–2017 (2014).

157. H.-Y. Cho, W. Wang, N. Jhaveri, S. Torres, J. Tseng, M. N. Leong, D. J. Lee, A. Goldkorn,T. Xu, N. A. Petasis, S. G. Louie, A. H. Schönthal, F. M. Hofman, T. C. Chen, Perillylalcohol for the treatment of temozolomide-resistant gliomas. Mol. Cancer Ther. 11,2462–2472 (2012).

158. C. O. Da Fonseca, I. Petrone Soares, D. S. Clemençon, S. Rochlin, L. Cardeman,T. Quirico-Santos, Long-term outcome in patients with recurrent malignant gliomatreated with Perillyl alcohol inhalation. Anticancer Res. 33, 5625–5631 (2013).

159. T. H. Kim, J. Song, S.-H. Kim, A. K. Parikh, X. Mo, K. Palanichamy, B. Kaur, J. Yu, S. O. Yoon,I. Nakano, C.-H. Kwon, Piperlongumine treatment inactivates peroxiredoxin 4,exacerbates endoplasmic reticulum stress, and preferentially kills high-grade gliomacells. Neuro Oncol. 16, 1354–1364 (2014).

160. E. B. Golden, H.-Y. Cho, A. Jahanian, F. M. Hofman, S. G. Louie, A. H. Schönthal, T. C. Chen,Chloroquine enhances temozolomide cytotoxicity in malignant gliomas by blockingautophagy. Neurosurg. Focus 37, E12 (2014).

161. A. Yacoub, M. A. Park, D. Hanna, Y. Hong, C. Mitchell, A. P. Pandya, H. Harada, G. Powis,C.-S. Chen, C. Koumenis, S. Grant, P. Dent, OSU-03012 promotes caspase-independentbut PERK-, cathepsin B-, BID-, and AIF-dependent killing of transformed cells.Mol. Pharmacol. 70, 589–603 (2006).

162. L. Booth, J. L. Roberts, N. Cruickshanks, S. Tavallai, T. Webb, P. Samuel, A. Conley,B. Binion, H. F. Young, A. Poklepovic, S. Spiegel, P. Dent, PDE5 inhibitorsenhance celecoxib killing in multiple tumor types. J. Cell. Physiol. 230, 1115–1127(2015).

163. S. Koncarevic, S. Urig, K. Steiner, S. Rahlfs, C. Herold-Mende, H. Sueltmann, K. Becker,Differential genomic and proteomic profiling of glioblastoma cells exposed toterpyridineplatinum(II) complexes. Free Radic. Biol. Med. 46, 1096–1108 (2009).

164. J. Noack, J. Choi, K. Richter, A. Kopp-Schneider, A. Régnier-Vigouroux, A sphingosinekinase inhibitor combined with temozolomide induces glioblastoma cell death throughaccumulation of dihydrosphingosine and dihydroceramide, endoplasmic reticulumstress and autophagy. Cell Death Dis. 5, e1425 (2014).

165. B. Zhang, S. Shah, J. Prince, W. Walters, A. Bregy, Y. Guo, R. J. Komatar, R. M. Graham,ET-71 the antitumor effects of withaferin a in glioblastoma stem cells. Neuro Oncol.16, v94–v95 (2014).

166. K. Heminger, V. Jain, M. Kadakia, B. Dwarakanath, S. J. Berberich, Altered gene expressioninduced by ionizing radiation and glycolytic inhibitor 2-deoxy-glucose in a human gliomacell line: Implications for radio sensitization. Cancer Biol. Ther. 5, 815–823 (2006).

167. A. Jalota, M. Kumar, B. C. Das, A. K. Yadav, K. Chosdol, S. Sinha, Synergistic increase inefficacy of a combination of 2-deoxy-D-glucose and cisplatin in normoxia and hypoxia:Switch from autophagy to apoptosis. Tumour Biol. 37, 12347–12358 (2016).

168. A. Marcilla-Etxenike, M. L. Martin, M. A. Noguera-Salvà, J. M. García-Verdugo,M. Soriano-Navarro, I. Dey, P. V. Escribà, X. Busquets, 2-Hydroxyoleic acid inducesER stress and autophagy in various human glioma cell lines. PLOS ONE 7, e48235(2012).

169. W. Jia, R. M. Loria, M. A. Park, A. Yacoub, P. Dent, M. R. Graf, The neuro-steroid,5-androstene 3b,17a diol; induces endoplasmic reticulum stress and autophagy throughPERK/eIF2a signaling in malignant glioma cells and transformed fibroblasts. Int. J.Biochem. Cell Biol. 42, 2019–2029 (2010).

170. I. Y. Kim, Y. J. Kang, M. J. Yoon, E. H. Kim, S. U. Kim, T. K. Kwon, I. A. Kim, K. S. Choi,Amiodarone sensitizes human glioma cells but not astrocytes to TRAIL-inducedapoptosis via CHOP-mediated DR5 upregulation. Neuro Oncol. 13, 267–279 (2011).

171. T. Horibe, A. Torisawa, M. Kohno, K. Kawakami, Molecular mechanism of cytotoxicityinduced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells. Mol. Cancer11, 59 (2012).

172. K. S. Eom, H.-J. Kim, H. S. So, R. Park, T. Y. Kim, Berberine-induced apoptosis in humanglioblastoma T98G cells is mediated by endoplasmic reticulum stress accompanyingreactive oxygen species and mitochondrial dysfunction. Biol. Pharm. Bull. 33, 1644–1649(2010).

173. T.-C. Chen, K.-C. Lai, J.-S. Yang, C.-L. Liao, T.-C. Hsia, G.-W. Chen, J.-J. Lin, H.-J. Lin,T.-H. Chiu, Y.-J. Tang, J.-G. Chung, Involvement of reactive oxygen species and caspase-dependent pathway in berberine-induced cell cycle arrest and apoptosis in C6 ratglioma cells. Int. J. Oncol. 34, 1681–1690 (2009).

16 of 18

Page 17: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

SC I ENCE S I GNAL ING | R EV I EW

on March 7, 2021

http://stke.sciencemag.org/

Dow

nloaded from

174. S. Shen, Y. Zhang, Z. Wang, R. Liu, X. Gong, Bufalin induces the interplay betweenapoptosis and autophagy in glioma cells through endoplasmic reticulum stress. Int. J.Biol. Sci. 10, 212–224 (2014).

175. D. Trisciuoglio, B. Uranchimeg, J. H. Cardellina, T. L. Meragelman, S. Matsunaga,N. Fusetani, D. Del Bufalo, R. H. Shoemaker, G. Melillo, Induction of apoptosis in humancancer cells by candidaspongiolide, a novel sponge polyketide. J. Natl. Cancer Inst. 100,1233–1246 (2008).

176. S. Boridy, P. U. Le, K. Petrecca, D. Maysinger, Celastrol targets proteostasis and actssynergistically with a heat-shock protein 90 inhibitor to kill human glioblastoma cells.Cell Death Dis. 5, e1216 (2014).

177. K. Suzuki, A. Gerelchuluun, Z. Hong, L. Sun, J. Zenkoh, T. Moritake, K. Tsuboi, Celecoxibenhances radiosensitivity of hypoxic glioblastoma cells through endoplasmic reticulumstress. Neuro Oncol. 15, 1186–1199 (2013).

178. Y. Qian, Y. Zheng, L. Abraham, K. S. Ramos, E. Tiffany-Castiglioni, Differential profiles ofcopper-induced ROS generation in human neuroblastoma and astrocytoma cells.Brain Res. Mol. Brain Res. 134, 323–332 (2005).

179. P. Ravanan, R. Sano, P. Talwar, S. Ogasawara, S.-i. Matsuzawa, M. Cuddy, S. K. Singh,G. S. R. Rao, P. Kondaiah, J. C. Reed, Synthetic triterpenoid cyano enone of methylboswellate activates intrinsic, extrinsic, and endoplasmic reticulum stress cell deathpathways in tumor cell lines. Mol. Cancer Ther. 10, 1635–1643 (2011).

180. J.-M. Pan, L. Zhou, G.-B. Wang, G.-W. Xia, K. Xue, X.-G. Cui, H.-Z. Shi, J. H. Liu, J. Hu,Fatsioside A inhibits the growth of glioma cells via the induction of endoplasmicreticulum stress-mediated apoptosis. Mol. Med. Rep. 11, 3493–3498 (2015).

181. J. Ma, Y.-R. Yang, W. Chen, M.-H. Chen, H. Wang, X.-D. Wang, L.-L. Sun, F.-Z. Wang,D.-C. Wang, Fluoxetine synergizes with temozolomide to induce the CHOP-dependentendoplasmic reticulum stress-related apoptosis pathway in glioma cells. Oncol. Rep. 36,676–684 (2016).

182. M.-S. Hwang, W.-K. Baek, Glucosamine induces autophagic cell death through thestimulation of ER stress in human glioma cancer cells. Biochem. Biophys. Res. Commun.399, 111–116 (2010).

183. P. Pyrko, A. Kardosh, W. Wang, W. Xiong, A. H. Schönthal, T. C. Chen, HIV-1 proteaseinhibitors nelfinavir and atazanavir induce malignant glioma death by triggeringendoplasmic reticulum stress. Cancer Res. 67, 10920–10928 (2007).

184. W.-T. Liu, C.-Y. Huang, I.-C. Lu, P.-W. Gean, Inhibition of glioma growth by minocycline ismediated through endoplasmic reticulum stress-induced apoptosis and autophagic celldeath. Neuro Oncol. 15, 1127–1141 (2013).

185. Y.-C. Chou, M.-Y. Chang, M.-J. Wang, T. Harnod, C.-H. Hung, H.-T. Lee, C.-C. Shen,J.-G. Chung, PEITC induces apoptosis of Human Brain Glioblastoma GBM8401 Cellsthrough the extrinsic- and intrinsic -signaling pathways. Neurochem. Int. 81, 32–40(2015).

186. Y.-C. Chou, M.-Y. Chang, M.-J. Wang, H.-C. Liu, S.-J. Chang, T. Harnod, C.-H. Hung,H.-T. Lee, C.-C. Shen, J.-G. Chung, Phenethyl isothiocyanate alters the gene expressionand the levels of protein associated with cell cycle regulation in human glioblastomaGBM 8401 cells. Environ. Toxicol. 32, 176–187 (2015).

187. Y.-C. Chou, M.-Y. Chang, M.-J. Wang, F.-S. Yu, H.-C. Liu, T. Harnod, C.-H. Hung, H.-T. Lee,J.-G. Chung, PEITC inhibits human brain glioblastoma GBM 8401 cell migration andinvasion through the inhibition of uPA, Rho A, and Ras with inhibition of MMP-2, -7 and-9 gene expression. Oncol. Rep. 34, 2489–2496 (2015).

188. M. J. Yoon, Y. J. Kang, I. Y. Kim, E. H. Kim, J. A. Lee, J. H. Lim, T. K. Kwon, K. S. Choi,Monensin, a polyether ionophore antibiotic, overcomes TRAIL resistance in glioma cellsvia endoplasmic reticulum stress, DR5 upregulation and c-FLIP downregulation.Carcinogenesis 34, 1918–1928 (2013).

189. D.-Y. Lu, C.-S. Chang, W.-L. Yeh, C.-H. Tang, C.-W. Cheung, Y.-M. Leung, J.-F. Liu,K.-L. Wong, The novel phloroglucinol derivative BFP induces apoptosis of glioma cancerthrough reactive oxygen species and endoplasmic reticulum stress pathways.Phytomedicine 19, 1093–1100 (2012).

190. E. B. Golden, H.-Y. Cho, F. M. Hofman, S. G. Louie, A. H. Schönthal, T. C. Chen, Quinoline-basedantimalarial drugs: A novel class of autophagy inhibitors. Neurosurg. Focus 38, E12 (2015).

191. J.-t. Zhong, Y. Xu, H.-w. Yi, J. Su, H.-m. Yu, X.-y. Xiang, X.-n. Li, Z.-c. Zhang, L.-k. Sun, TheBH3 mimetic S1 induces autophagy through ER stress and disruption of Bcl-2/Beclin1 interaction in human glioma U251 cells. Cancer Lett. 323, 180–187 (2012).

192. C. H. Kuder, R. M. Sheehy, J. D. Neighbors, D. F. Wiemer, R. J. Hohl, Functional evaluationof a fluorescent schweinfurthin: Mechanism of cytotoxicity and intracellularquantification. Mol. Pharmacol. 82, 9–16 (2012).

193. M. C. White, G. G. Johnson, W. Zhang, J. V. Hobrath, G. A. Piazza, M. Grimaldi, Sulindacsulfide inhibits sarcoendoplasmic reticulum Ca2+ ATPase, induces endoplasmicreticulum stress response, and exerts toxicity in glioma cells: Relevant similarities to andimportant differences from celecoxib. J. Neurosci. Res. 91, 393–406 (2013).

194. O. Antal, L. Hackler Jr., J. Shen, I. Mán, K. Hideghéty, K. Kitajka, L. G. Puskás,Combination of unsaturated fatty acids and ionizing radiation on human gliomacells: Cellular, biochemical and gene expression analysis. Lipids Health Dis. 13, 142(2014).

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

195. C. Biray Avci, C. C. Kurt, B. E. Tepedelen, O. Ozalp, B. Goker, Z. Mutlu, Y. Dodurga,L. Elmas, C. Gunduz, Zoledronic acid induces apoptosis via stimulating theexpressions of ERN1, TLR2, and IRF5 genes in glioma cells. Tumour Biol. 37, 6673–6679(2016).

196. S. Shen, Y. Zhang, R. Zhang, X. Tu, X. Gong, Ursolic acid induces autophagy in U87MGcells via ROS-dependent endoplasmic reticulum stress. Chem. Biol. Interact. 218, 28–41(2014).

197. M. Cattaneo, S. Baronchelli, D. Schiffer, M. Mellai, V. Caldera, G. J. Saccani, L. Dalpra,A. Daga, R. Orlandi, P. DeBlasio, I. Biunno, Down-modulation of SEL1L, an unfoldedprotein response and endoplasmic reticulum-associated degradation protein, sensitizesglioma stem cells to the cytotoxic effect of valproic acid. J. Biol. Chem. 289, 2826–2838(2014).

198. C. D. Bown, J.-F. Wang, L. T. Young, Increased expression of endoplasmic reticulumstress proteins following chronic valproate treatment of rat C6 glioma cells.Neuropharmacology 39, 2162–2169 (2000).

199. C. F. Tsai, W. L. Yeh, S. M. Huang, T. W. Tan, D. Y. Lu, Wogonin induces reactive oxygenspecies production and cell apoptosis in human glioma cancer cells. Int. J. Mol. Sci. 13,9877–9892 (2012).

200. J. A. Rubiolo, H. López-Alonso, P. Martinez, A. Millán, E. Cagide, M. R. Vieytes, F. V. Vega,L. M. Botana, Yessotoxin induces ER-stress followed by autophagic cell death in gliomacells mediated by mTOR and BNIP3. Cell Signal. 26, 419–432 (2013).

201. J.-F. Wang, C. Bown, L. T. Young, Differential display PCR reveals novel targets for themood-stabilizing drug valproate including the molecular chaperone GRP78.Mol. Pharmacol. 55, 521–527 (1999).

202. I. A. Ciechomska, B. Kaminska, ER stress and autophagy contribute to CsA-induced deathof malignant glioma cells. Autophagy 8, 1526–1528 (2012).

203. I. A. Ciechomska, K. Gabrusiewicz, A. A. Szczepankiewicz, B. Kaminska, Endoplasmicreticulum stress triggers autophagy in malignant glioma cells undergoing cyclosporineA-induced cell death. Oncogene 32, 1518–1529 (2013).

204. J. Ma, L.-N. Hou, Z.-X. Rong, P. Liang, C. Fang, H.-F. Li, H. Qi, H.-Z. Chen, Antidepressantdesipramine leads to C6 glioma cell autophagy: Implication for the adjuvant therapy ofcancer. Anticancer Agents Med Chem. 13, 254–260 (2013).

205. J. Ma, Y. Qiu, L. Yang, L. Peng, Z. Xia, L.-N. Hou, C. Fang, H. Qi, H.-Z. Chen, Desipramineinduces apoptosis in rat glioma cells via endoplasmic reticulum stress-dependent CHOPpathway. J. Neurooncol. 101, 41–48 (2011).

206. K.-P. Hsieh, N. Wilke, A. Harris, M. F. Miles, Interaction of ethanol with inducers ofglucose-regulated stress proteins. Ethanol potentiates inducers of grp78 transcription.J. Biol. Chem. 271, 2709–2716 (1996).

207. M. F. Miles, N. Wilke, M. Elliot, W. Tanner, S. Shah, Ethanol-responsive genes in neuralcells include the 78-kilodalton glucose-regulated protein (GRP78) and 94-kilodaltonglucose-regulated protein (GRP94) molecular chaperones. Mol. Pharmacol. 46, 873–879(1994).

208. Y. Qian, Y. Zheng, K. S. Ramos, E. Tiffany-Castiglioni, GRP78 compartmentalizedredistribution in Pb-treated glia: Role of GRP78 in lead-induced oxidative stress.Neurotoxicology 26, 267–275 (2005).

209. Y. Qian, M. H. Falahatpisheh, Y. Zheng, K. S. Ramos, E. Tiffany-Castiglioni, Induction of 78 kDglucose-regulated protein (GRP78) expression and redox-regulated transcription factoractivity by lead and mercury in C6 rat glioma cells. Neurotox. Res. 3, 581–589 (2001).

210. L. Romero-Ramírez, I. García-Álvarez, J. Casas, M. A. Barreda-Manso, N. Yanguas-Casás,M. Nieto-Sampedro, A. Fernández-Mayoralas, New oleyl glycoside as anti-cancer agentthat targets on neutral sphingomyelinase. Biochem. Pharmacol. 97, 158–172 (2015).

211. L. Zhang, X. Tong, J. Zhang, J. Huang, J. Wang, DAW22, a natural sesquiterpenecoumarin isolated from Ferula ferulaeoides (Steud.) Korov. that induces C6 glioma cellapoptosis and endoplasmic reticulum (ER) stress. Fitoterapia 103, 46–54 (2015).

212. R. Stupp, M. E. Hegi, W. P. Mason, M. J. van den Bent, M. J. Taphoorn, R. C. Janzer,S. K. Ludwin, A. Allgeier, B. Fisher, K. Belanger, P. Hau, A. A. Brandes, J. Gijtenbeek,C. Marosi, C. J. Vecht, K. Mokhtari, P. Wesseling, S. Villa, E. Eisenhauer, T. Gorlia, M. Weller,D. Lacombe, J. G. Cairncross, R.-O. Mirimanoff ; European Organisation for Research andTreatment of Cancer Brain Tumour and Radiation Oncology Groups, National CancerInstitute of Canada Clinical Trials Group, Effects of radiotherapy with concomitant andadjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in arandomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10,459–466 (2009).

213. S. Sun, D. Lee, A. S. W. Ho, J. K. S. Pu, X. Q. Zhang, N. P. Lee, P. J. R. Day, W. M. Lui,C. F. Fung, G. K. K. Leung, Inhibition of prolyl 4-hydroxylase, beta polypeptide (P4HB)attenuates temozolomide resistance in malignant glioma via the endoplasmic reticulumstress response (ERSR) pathways. Neuro Oncol. 15, 562–577 (2013).

214. M. Mellai, M. Cattaneo, A. M. Storaci, L. Annovazzi, P. Cassoni, A. Melcarne, P. De Blasio,D. Schiffer, I. Biunno, SEL1L SNP rs12435998, a predictor of glioblastoma survival andresponse to radio-chemotherapy. Oncotarget 6, 12452–12467 (2015).

215. T. Okunaga, Y. Urata, S. Goto, T. Matsuo, S. Mizota, K. Tsutsumi, I. Nagata, T. Kondo,Y. Ihara, Calreticulin, a molecular chaperone in the endoplasmic reticulum,

17 of 18

Page 18: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

SC I ENCE S I GNAL ING | R EV I EW

modulates radiosensitivity of human glioblastoma U251MG cells. Cancer Res. 66,8662–8671 (2006).

216. Cancer Genome Atlas Research Network, Comprehensive genomic characterizationdefines human glioblastoma genes and core pathways. Nature 455, 1061–1068(2008).

217. E. Xipell, T. Aragón, N. Martínez-Velez, B. Vera, M. A. Idoate, J. J. Martínez-Irujo,A. G. Garzón, M. Gonzalez-Huarriz, A. M. Acanda, C. Jones, F. F. Lang, J. Fueyo,C. Gomez-Manzano, M. M. Alonso, Endoplasmic reticulum stress-inducing drugssensitize glioma cells to temozolomide through downregulation of MGMT, MPG,and Rad51. Neuro Oncol. 18, 1109–1119 (2016).

218. A.-L. Huber, J. Lebeau, P. Guillaumot, V. Pétrilli, M. Malek, J. Chilloux, F. Fauvet, L. Payen,A. Kfoury, T. Renno, E. Chevet, S. N. Manié, p58IPK-mediated attenuation of theproapoptotic PERK-CHOP pathway allows malignant progression upon low glucose.Mol. Cell 49, 1049–1059 (2013).

219. B. Mollereau, N. M. Rzechorzek, B. D. Roussel, M. Sedru, D. M. Van den Brink,B. Bailly-Maitre, F. Palladino, D. B. Medinas, P. M. Domingos, S. Hunot, S. Chandran,S. Birman, T. Baron, D. Vivien, C. B. Duarte, H. D. Ryoo, H. Steller, F. Urano, E. Chevet,G. Kroemer, A. Ciechanover, E. J. Calabrese, R. J. Kaufman, C. Hetz, Adaptivepreconditioning in neurological diseases—Therapeutic insights from proteostaticperturbations. Brain Res. 1648, 603–616 (2016).

Obacz et al., Sci. Signal. 10, eaal2323 (2017) 14 March 2017

Funding: This work was supported by grants from the French National Cancer Institute (INCaPLBIO: 2015-111 and INCA_7981) and by la Ligue contre le Cancer (to E.C.), the MSCA 2017RISE–INSPIRED grant, and an ECOS–CONICYT grant (to E.C. and C.H.). We also thank the FondoNacional de Desarrollo Científico y Tecnológico (FONDECYT) no. 1140549, the MillenniumInstitute no. P09-015-F, FONDAP 15150012 (to C.H.), and FONDECYT no. 3160461 (to H.U.). Wealso thank the Alzheimer’s Association, CONICYT grant USA2013-0003, the Frick Foundation,Amyotrophic Lateral Sclerosis (ALS) Therapy Alliance, and the Michael J. Fox Foundation forParkinson’s disease research FONDEF D11E1007, FONDEF ID16I10223, Office of Naval ResearchGlobal N62909-16-1-2003, and ALS Research Program Therapeutic Idea Award AL150111 (toC.H.). J.O. was supported by a postdoctoral fellowship from “Région Bretagne.” Competinginterests: The authors declare that they have no competing interests.

Submitted 18 October 2016Accepted 21 December 2016Published 14 March 201710.1126/scisignal.aal2323

Citation: J. Obacz, T. Avril, P.-J. Le Reste, H. Urra, V. Quillien, C. Hetz, E. Chevet, Endoplasmicreticulum proteostasis in glioblastoma—From molecular mechanisms to therapeuticperspectives. Sci. Signal. 10, eaal2323 (2017).

18 of 18

on March 7, 2021

http://stke.sciencemag.org/

Dow

nloaded from

Page 19: Endoplasmic reticulum proteostasis in glioblastoma From … · Glioblastomas [GBMs; World Health Organization (WHO) grade IV gliomas] represent the most frequent and malignant form

therapeutic perspectivesFrom molecular mechanisms to−−Endoplasmic reticulum proteostasis in glioblastoma

Joanna Obacz, Tony Avril, Pierre-Jean Le Reste, Hery Urra, Véronique Quillien, Claudio Hetz and Eric Chevet

DOI: 10.1126/scisignal.aal2323 (470), eaal2323.10Sci. Signal. 

ARTICLE TOOLS http://stke.sciencemag.org/content/10/470/eaal2323

CONTENTRELATED

http://stke.sciencemag.org/content/sigtrans/11/559/eaaw2150.fullhttp://science.sciencemag.org/content/sci/355/6330/1163.fullhttp://stke.sciencemag.org/content/sigtrans/11/516/eaat1772.fullhttp://stke.sciencemag.org/content/sigtrans/11/511/eaan0630.fullhttp://stke.sciencemag.org/content/sigtrans/10/508/eaar6316.fullhttp://stke.sciencemag.org/content/sigtrans/10/499/eaaq0229.fullhttp://stke.sciencemag.org/content/sigtrans/10/493/eaao7014.fullhttp://stke.sciencemag.org/content/sigtrans/10/490/eaao5008.fullhttp://stke.sciencemag.org/content/sigtrans/10/489/eaao4313.fullhttp://stke.sciencemag.org/content/sigtrans/10/483/eaao0437.fullhttp://stke.sciencemag.org/content/sigtrans/10/482/eaai7814.fullhttp://stke.sciencemag.org/content/sigtrans/10/482/eaah7177.fullhttp://stke.sciencemag.org/content/sigtrans/10/473/eaan3515.fullhttp://stke.sciencemag.org/content/sigtrans/10/471/eaan2405.fullhttp://stke.sciencemag.org/content/sigtrans/10/470/eaan0430.fullhttp://stke.sciencemag.org/content/sigtrans/10/470/eaan1418.fullhttp://stke.sciencemag.org/content/sigtrans/8/397/ra98.fullhttp://stke.sciencemag.org/content/sigtrans/8/378/ra52.fullhttp://stke.sciencemag.org/content/sigtrans/8/382/ra62.fullhttp://stke.sciencemag.org/content/sigtrans/8/374/rs5.fullhttp://stke.sciencemag.org/content/sigtrans/9/426/ra44.fullhttp://stke.sciencemag.org/content/sigtrans/10/470/eaaf7593.full

REFERENCES

http://stke.sciencemag.org/content/10/470/eaal2323#BIBLThis article cites 219 articles, 68 of which you can access for free

PERMISSIONS http://www.sciencemag.org/help/reprints-and-permissions

Terms of ServiceUse of this article is subject to the

is a registered trademark of AAAS.Science SignalingYork Avenue NW, Washington, DC 20005. The title (ISSN 1937-9145) is published by the American Association for the Advancement of Science, 1200 NewScience Signaling

Copyright © 2017, American Association for the Advancement of Science

on March 7, 2021

http://stke.sciencemag.org/

Dow

nloaded from