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Chapter 7: Mechanisms of Cell Death
Mechanisms of Cell Death: Introduction
Cell death has historically been subdivided into genetically controlled (or programmed) and
unregulated mechanisms. Apoptosis has been recognized as a fundamental type of
programmed cell death that is activated and repressed by specific genes and pathways. In
contrast, necrosis has traditionally been considered an unregulated process and the result of
cell death by acute physical trauma or overwhelming stress that is incompatible with cell
survival. More recently, however, this strict classification of cell death mechanisms has been
revisited, as mechanisms considered programmed were in certain instances shown to
modulate necrosis and result in a regulated nonapoptotic cell death displaying necrotic
morphology (necroptosis). It is also becoming apparent that disabling programmed cell death
reveals novel survival mechanisms such as the catabolic autophagy pathway used by cancer
cells to tolerate stress and starvation. Thus, cancer cells that acquire defects in programmed
cell death are not merely undead but rather mobilize a novel physiologic state that actively
enables survival. We review here the key aspects of the different cell death mechanisms and
their regulation, and how they impact cancer development, progression, and treatment
response.
Apoptosis
Apoptosis (or type I programmed cell death) is a genetic pathway for rapid and efficient
killing of unnecessary or damaged cells that was initially described by Vogt (1842), and then
Kerr et al.1and Wyllie et al.2They detailed a novel morphologic process for cell death that
included swiftly executed cell shrinkage, blebbing of the plasma membrane, chromatin
condensation, and intranucleosomal DNA fragmentation, after which cell corpses are
engulfed by neighboring cells and professional phagocytes and degraded. Apoptosis
(commonly pronounced ap-a-tow-sis), a term coined from the Greek apoor from,
andptosisor falling, to make the analogy of leaves falling off a tree. Although
underappreciated at the time, once the genes that controlled apoptosis were identified in
model organisms and humans, and it was shown that perturbation of this program disturbed
development and provoked disease, the importance of apoptosis was generally realized.
Cell death by apoptosis is involved in sculpting tissues in normal development. These
developmental cell deaths span the removal of the interdigital webs and tadpole tails, to
selection for and against specific B- and T-cell populations essential for controlling the
immune response. Proper regulation of apoptosis is critical in that excessive apoptosis is
associated with degenerative conditions, while deficient apoptosis promotes autoimmunity
and cancer. Furthermore, apoptosis is required for eliminating damaged or pathogen-infected
cells as a mechanism for limiting disease, especially cancer. In turn, tumors and pathogens
have also evolved elegant mechanisms for disabling apoptosis to facilitate their persistence,
often promoting disease progression. In human cancers, multiple mechanisms to disable
apoptosis include loss of function of the apoptosis-promotingp53tumor suppressor and gain
of function of the apoptosis-inhibitory and oncogenic B-cell chronic lymphocytic
leukemia/lymphoma 2 (BCL2). It became apparent then that cancer progression was aided
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not only by increasing the rate of cell multiplication through activation of the c-
myconcogene, for example, but also by decreasing the rate of cell elimination through
apoptosis, exemplified by gain of BCL2expression (Fig.7.1). Indeed, activation of oncogenes
such as c-mycor E1A,35or loss of tumor suppressor genes such as Rb,6can promote
apoptosis, providing an explanation for the necessity for inactivation of the apoptoticpathway in many tumors. This may create a physiological state of cancer cells being primed
for death where the necessity to up-regulate antiapoptotic mechanisms such as BCL2 to
oppose oncogene activation poises cancer cells to reactivation of apoptosis providing a
therapeutic window for cancer therapy.7
Figure 7.1. Tumor progression through cooperation of proliferative and
antiapoptotic functions.
In normal cells in epithelial tissues (green cells) initiating mutational events such as
deregulation of c-mycexpression deregulate cell growth control and promote abnormal cell
proliferation (yellow cells) while triggering a proapoptotic tumor suppression (red apoptotic
cells) mechanism that can restrict tumor expansion. Subsequent acquisition of mutations
that disables the apoptotic response, exemplified by Bcl-2overexpression, prevents this
effective means of culling emerging tumor cells, thereby favoring tumor expansion. Similar
oncogenic events occur in lymphoid tissues.
The effectiveness of many existing anticancer drugs involves or is facilitated by triggering the
apoptotic response. Thus, a detailed understanding of the components, molecular signaling
events, and control points in the apoptotic pathway has enabled rational approaches to
chemotherapy aimed at restoring the capacity for apoptosis to tumor cells. Identification of
the molecular means by which tumors inactivate apoptosis has led to cancer therapies
directly targeting the apoptotic pathway. These drugs are now being used in the clinic to
specifically reactivate apoptosis in tumor cells in which it is disabled to achieve tumor
regression.
Model Organisms Provide Mechanistic Insight into Apoptosis Regulation
Key to elevating the field of programmed cell death from a descriptive to a mechanism-based
process was the discovery of genes in the nematode Ceanorhabditis elegansthat control cell
death, the cell death defective or cedgenes.8Genetic analysis revealed that ced-4and ced-
3promote cell death, as worms with defective mutations in these genes possessed extra
cells. In contrast, the ced-9gene inhibited the death-promoting function of ced-4and ced-3,
thereby maintaining cell viability.9ced-9in turn was inhibited by egl-1, thereby promoting
cell death. This creates a linear genetic pathway controlled upstream by cell-specific death
specification regulators, and downstream by cell corpse engulfment and degradation
mechanisms (Fig.7.2).10These findings helped propel work in mammalian systems when it
became apparent that Ced-9 was homologous to BCL2,11Ced-3 was homologous to
interleukin1-converting enzyme, a cysteine protease that would later be classified as a
member of the caspase family of aspartic acid proteases,12Egl-1 was a BH3-only protein
homologue,10and that the proapoptotic factor apoptotic protease-activating factor (APAF-1)-1 identified in mammals was homologous to Ced-4.13
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Figure 7.2. Analogous pathways regulate programmed cell death/apoptosis in
metazoans.
Regulation of programmed cell death in the nematodeCeanorhabditis elegans(top) andregulation of apoptosis in mammals (bottom). Shaded regions highlight corresponding
homologous genes and protein families. In C. elegans, numerous cell death specification
genes can up-regulate the transcription of the BH3-only protein Egl-1, which interacts with
the antiapoptotic Bcl-2 homologue Ced-9 inhibiting is interaction with Ced-4. Ced-4, the
Apaf-1 homologue, in turn, activates the caspase Ced-3, leading to cell death. A variety of
engulfment gene products are then responsible for apoptotic corpse elimination and
nucleases degrade the genome. In mammals, many survival, damage, and stress events
impinge on the numerous members of the BH3-only class of proapoptotic proteins to either
activate them to promote apoptosis or suppress their activation to enable cell survival. BH3-
only proteins interact with and antagonize the numerous Bcl-2-related multidomain
antiapoptotic proteins that serve to sequester proapoptotic Bax and Bak and may also
contribute directly to Bax/Bak activation. Bax or Bak is essential for signaling apoptosis by
permeabilizing the outer mitochondrial membrane to allow the release of cytochrome cand
second mitochondrial-derived activator of caspase (SMAC). Cytochromecacts as a cofactor
for Apaf-1-mediated caspase activation in the apoptosome, and the SMAC amino-terminal
four amino acids bind and antagonize the inhibitors of apoptosis proteins that interact with
and suppress caspases, leading to their activation, widespread substrate cleavage, and cell
death. Many engulfment gene products are responsible for corpse elimination and caspase-
activated nucleases in the apoptotic cell itself, and additional nucleases within the engulfing
cell are responsible for degradation of the genome.
A similar cell death pathway in the fruit fly Drosophila melanogasteridentified Reaper, Hid
and Grim as inhibitors of the inhibitors of apoptosis proteins (IAPs) that negatively regulate
caspase activation. This eventually led to the identification of their mammalian counterpart
second mitochondrial-derived activator of caspase (SMAC), also known as direct IAP-binding
protein with low pI (DIABLO).14These and other studies established the paradigm whereby
proapoptotic BH3-only proteins inhibit antiapoptotic Bcl-2 proteins that prevent APAF-1-
mediated caspase activation suppressed by IAPs, and the caspase-mediated proteolytic
cellular destruction leads rapidly to cell death. It would later be realized that in mammals
BH3-only proteins could also act as direct activators of the proapoptotic machinery (see later
discussion).
Discovery of Bcl-2 and its Role as an Apoptosis Inhibitor in B-cell
Lymphoma
To identify mechanisms of oncogenesis, the bcl-2gene was cloned from the site of frequent
chromosome translocation t(14;18):(q32;q21) in human follicular lymphoma.1517This
chromosome rearrangement places bcl-2under the transcriptional control of the
immunoglobulin heavy chain locus causing abnormally high levels of bcl-2expression.
Distinct from other oncogenes at the time, instead of promoting cell proliferation, bcl-2promoted B-cell tumorigenesis by the novel concept of providing a survival advantage to
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cells stimulated to proliferate by c-myc.18Indeed, engineering high Bcl-2 expression in the
lymphoid compartment in mutant mice promotes follicular hyperplasia that progresses to
lymphoma upon c-myctranslocation, and bcl-2synergizes with c-mycto produce lymphoid
tumors, paralleling events in human follicular lymphoma.19,20Bcl-2 localizes to
mitochondria where it has broad activity in promoting cell survival through suppression ofapoptosis,21provoked by numerous events, including oncogene activation (c-myc, E1A),
tumor suppressor activation (p53), growth factor and cytokine limitation, and cellular
damage. It also became clear that inactivation of the retinoblastoma tumor suppressor (Rb)
pathway promotes ap53-mediated apoptotic response, suggesting that apoptosis was part of
a tumor suppression mechanism that responded to deregulation of cell
growth.6,22,23Indeed, apoptotic defects acquired by a variety of means are a common
event in human tumorigenesis.
Control of Apoptosis by Bcl-2 Family Members
Bcl-2 is the first member of what is now a large family of related proteins that regulateapoptosis and are conserved among metazoans including worms, flies, and mammals, and
also viruses.2428Multidomain Bcl-2 family members containing Bcl-2 homology regions 1-4
(BH1-4) are either antiapoptotic (Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and Bfl-1/A1, and virally
encoded Bcl-2 homologues such as E1B 19K), or proapoptotic (Bax and Bak). Antiapoptotic
proteins can block apoptosis by binding and sequestering Bax and Bak or by indirectly
preventing Bax and Bak activation (Fig.7.3).25,29,30
Figure 7.3. Regulation of apoptosis by the Bcl-2 family of proteins in mammals.
A:Schematic of apoptosis regulation by the Bcl-2 family. Cytotoxic events activate, while
survival signaling events suppress the activity of the BH3-only class of Bcl-2 family members
(orange). BH3-only proteins are controlled at the transcription level and also by numerous
posttranscriptional events that modulate phosphorylation, proteolysis, localization,
sequestration, and protein stability. Once activated, BH3-only proteins disrupt functional
sequestration of Bak and Bax by the multidomain antiapoptotic Bcl-2-like proteins (blue) and
may also directly facilitate Bax/Bak activation. Although Bak is commonly membrane-
associated in a complex with Mcl-1 and Bcl-xLin healthy cells, Bax resides in the cytoplasm
as an inactive monomer with its carboxy-terminus occluding the BH3-binding hydrophobic
cleft.138Bax activation thereby additionally requires a change in protein conformation and
membrane translocation by an unknown mechanism that may be facilitated by tBid binding.
Binding specificity among BH3-only proteins for antiapoptotic Bcl-2-like proteins determines
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which complexes are disrupted, with some BH3-only proteins having broad specificity and
others do not. Survival and death signaling events can also modulate apoptosis by targeting
the multidomain antiapoptotic proteins either by antagonizing their function to promote
apoptosis or induction their function to promote survival. ABT-737 is a rationally designed
BAD BH3 mimetic that can bind Bcl-2, Bcl-xL, and Bcl-w but not Mcl-1 that can promoteapoptosis where survival does not depend on Mcl-1. Once activated, Bax or Bak
oligomerization promotes apoptosis. B:Tumor necrosis factor-(TNF-) apoptotic signaling
induces mitochondrial membrane translocation and a conformational change exposing the
amino-terminus of Bax (visualized here by the Bax-NT antibody) and apoptosis, which is
blocked by sequestration of Bax by the antiapoptotic viral Bcl-2 homologue E1B 19K. The
human cancer cell line (HeLa cells) with or without E1B 19K expression, were then left
untreated or treated with TNF/CHX. The localization of conformationally altered Bax (Bax-NT)
and cytochrome c(left and middle panels), or E1B 19K and cytochrome c(right panel),
are shown. The proapoptotic stimulus (TNF/CHX) induces Bax activation, mitochondrial
translocation, and cytochrome crelease from mitochondria that leads to caspase activation
and apoptotic cell death, whereas expression of E1B 19K sequesters Bax thereby blocking
cytochrome crelease from mitochondria, caspase activation, and apoptotic cell death.
The yellowand redarrows, respectively, mark cells with partial or complete
cytochrome crelease from mitochondria upon TNF/CHX treatment.
Bax and Bak are functionally redundant and required for signaling apoptosis through
mitochondria, and deficiency in Bax and Bak produces a profound defect in apoptosis. Bax
and Bak are considered the core apoptosis machinery controlled directly or indirectly by
antiapoptotic Bcl-2-like proteins and proapoptotic BH3-only proteins. Remarkably, mice
deficient in both Bax and Bak develop relatively normally, suggesting that other deathmechanisms can compensate for loss of apoptosis in development.31In healthy cells, Bak is
bound and sequestered by Mcl-1 and Bcl-xLat cellular membranes, whereas Bax resides in
the cytosol in a latent form and requires activation and translocation to membranes, where it
is either sequestered by antiapoptotic Bcl-2-like proteins or otherwise induces apoptosis
(Fig.7.3).
Control of Multidomain Bcl-2 Family Proteins by the BH3-only Proteins
Bax and Bak deficiency abrogates the ability of BH3-only proteins to induce apoptosis,
placing them upstream and dependent on the core apoptosis machinery.32BH3-only protein
Bcl-2 family members (Bim, Bid, Nbk/Bik, Puma, Bmf, Bad, and Noxa) are proapoptotic and
antagonize the survival activity of antiapoptotic Bcl-2-like proteins by binding and displacing
Bax and Bak to allow apoptosis (BH3-only proteins as neutralizers of Bcl-2) (Fig.7.4).30The
different BH3-only proteins respond to specific stimuli to activate apoptosis (Fig.7.3). For
example, Bim induces apoptosis in response to taxanes, Puma and Noxa are transcriptional
targets of and mediate apoptosis in response top53activation, Bad signals apoptosis on
growth factor withdrawal, Nbk/Bik promotes apoptosis in response to inhibition of protein
synthesis, and Bid is required for apoptosis signaled by death receptors. All of these signals
are transduced from the BH3-only proteins to other members of the Bcl-2 family by protein-
protein interactions.
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Figure 7.4. Modes of apoptosis activation by BH3-only proteins.
The neutralization mode (top), de-repression mode (middle), and sensitizer mode
(bottom). See text for explanation.
The BH3 region of BH3-only proteins binds to a hydrophobic cleft in the multidomain Bcl-2-
like antiapoptotic proteins that also supports Bax and Bak binding,33,34causing their
displacement (neutralization mode; Fig.7.4).30Differential binding specificities among the
BH3 regions of the different BH3-only proteins determine whether they bind one or more Bcl-
2-like proteins and displace Bax or Bak or both.35Noxa binds and antagonizes Mcl-1,
whereas Bad binds and antagonizes Bcl-2 and Bcl-xL, necessitating cooperation between
Noxa and Bad function for efficient apoptosis. In contrast, Bim, Bid, and Puma have broader
binding specificity and antagonize Mcl-1, Bcl-2, and Bcl-xLto release both Bax and Bak to
induce apoptosis. Bim, the active form of Bid (truncated Bid or tBid) and possibly Puma can
also be direct activators of Bax and Bak. For example, tBid can bind to latent, inactive Bax
and promote its conformational change and translocation to the mitochondrial membrane
that is required for apoptosis.36BH3-only proteins can inhibit Bcl-2-like proteins, releasing
these direct activators of Bax and Bak to promote apoptosis in the de-repression mode
(Fig.7.4). BH3-only proteins that only interact with Bcl-2-like proteins can release activator
BH3-only proteins to promote apoptosis in the sensitizer mode (Fig.7.4). Thus, apoptosis
induction by BH3-only proteins can occur through neutralization, de-repression and sensitizer
functions.28
Importantly, it is this BH3 interaction with Bcl-2 that is the molecular basis for the BH3-
mimetic class of proapoptotic, Bcl-2antagonizing anticancer drugs (Fig.7.5).33,3739This
detailed understanding of the Bcl-2 family member protein interactions and function is
allowing rational, apoptosis-targeted therapy (see later discussion).
Figure 7.5. Three-dimensional structure of Bcl-xLwith bound Bad BH3 ligand and
ABT-737.
Space-filling model of Bcl-xLillustrating the hydrophobic cleft binding the 25-mer peptide
(green helix) of the Bad BH3 (left) or the rationally designed BH3-mimetic ABT-737 (right).
Role of Mitochondrial Membrane Permeabilization in Apoptosis
Once activated, Bax and Bak oligomerize in the mitochondrial outer membrane, rendering it
permeable to proapoptotic mitochondrial proteins cytochrome cand SMAC.4044How Bcl-2
family members permeabilize membranes is not entirely clear but it is likely related to a
change in topology of the proteins in the membrane and formation of a channel or pore.
Once released into the cytoplasm, cytochrome cinteracts with the WD40 domains of APAF-1
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Tumor necrosis factor-related ligand (TRAIL) and related death-promoting ligands engage
their cognate death receptors and activate caspase-8, which then cleaves Bid to active tBid.
tBid can bind Bcl-2 and related antiapoptotic proteins to release Bax and Bak and may also
directly promote their activation to permeabilize the mitochondrial outer membrane to
release the APAF-1 cofactor cytochrome c, and the inhibitors of apoptosis protein antagonistsecond mitochondrial-derived activator of caspase (SMAC) for promote caspase-9 and -3
activation and cell death. BH3-mimetics such as ABT-737 can promote apoptosis-induction
by TRAIL by relieving the protective capacity of the antiapoptotic Bcl-2-like proteins. In cells
that do not depend on the mitochondrial apoptotic signal, TRAIL-mediated caspase-8
activation can directly promote downstream caspase activation and can synergize with SMAC
mimetics in this case.
Drugs Targeting the Bcl-2 Family for Chemotherapy
In addition to Bcl-2 up-regulation in B-cell lymphoma as previously described, there are
other mechanisms for directly or indirectly inactivating apoptosis in tumors that facilitate
tumor progression and treatment resistance. Inactivation of thep53tumor suppressor, or
thep53pathway through the gain of function of thep53inhibitor MDM-2, is a common
occurrence in tumors that results in the loss of the proapoptotic and growth arrest functions
ofp53.57,58The BH3-only proteins Puma and Noxa are transcriptional targets ofp53, the
loss of which prevents induction of thep53-mediated response to genotoxic stress in tumors
as a mechanism of tumor suppression. Various means for restoration ofp53function in
tumors are, therefore, an attractive therapeutic approach.5961
Activation of the MAP kinase pathway is also common in tumors and results in stimulation of
tumor cell proliferation, but also the phosphorylation and proteasome mediated degradation
of the BH3-only protein Bim. This Bim inactivation promotes tumor growth, while also
producing resistance to the taxane class of chemotherapeutic drugs. This loss of Bim function
is rectified by blocking Bim degradation with a proteasome inhibitor (bortezomib)
(Fig.7.7).62Similarly, direct inhibition of MAP kinase pathway signaling with inhibitors
(sorafenib, UO126) can also restore apoptotic function in addition to suppressing the
proliferative response (Fig.7.7). Receptor tyrosine kinase pathway activation in tumors also
promotes tumor cell proliferation in part through MAP kinase pathway activation downstream
and in part through Bim and thereby apoptosis inactivation. In chronic myelogenous
leukemia in which chromosomal translocation and activation of the Bcr/Abl tyrosine kinase
also leads to BIM inhibition, blocking kinase signaling with imatinib mesylate restores Bim
and also Bad apoptotic function as a therapeutic strategy (Fig.7.7).63Activation of the PI-3
kinase pathway commonly through loss of PTENtumor suppressor function and AKT
activation results in phosphorylation and inactivation of the BH3-only protein Bad and
reduction of Bim transcription through inhibition of forkhead factors, resulting in down-
regulation of apoptosis.64Thus, inhibitors of the PI-3 kinase pathway can restore apoptosis
and facilitate tumor regression.65NF-B, a cytokine-responsive transcription factor, also
promotes tumor growth while turning on the expression of antiapoptotic regulators Bcl-xL,
Bfl-1 and IAPs (Fig.7.3).66Strategies to inhibit NF-B are likely to promote tumor regression
in part through restoration of apoptotic function.67
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Figure 7.7. Therapeutic regulation of Bim and the MAP kinase pathway in cancer
chemotherapy.
Bim protein stability is regulated by Erk phosphorylation and proteasome-mediated
degradation. Therapeutic modulation of the MAP kinase pathway (imatinib, sorafenib, and
UO126) or proteasome function (bortezomib) can restore Bim protein levels and apoptosis
function. Taxanes also stimulate Bim expression and promote Bim-mediated apoptosis,
synergizing with the aforementioned inhibitors.
Direct Modulation of Bcl-2 with BH3-mimeticsThe observation that antiapoptotic Bcl-2 family members bound and sequestered BH3-
regions in a hydrophobic cleft as a means to suppress apoptosis activation (Fig.7.5)
revealed the opportunity for the rational design of small molecules that occlude the cleft and
disrupt this Bcl-2-like protein/proapoptotic protein interaction, thereby promoting
apoptosis.33This was accomplished and resulted in ABT-737, which binds the BH3 binding
pocket of Bcl-2, Bcl-xL, and Bcl-w, but not Mcl-1, similarly to the Bcl-2 family protein binding
by Bad (Fig.7.5). ABT-737 exhibited activity as a single agent against human lymphoma and
small cell lung cancer cell lines in vitroand in mouse xenographs in vivo,37and in
combination with various cytotoxic agents against acute myeloid leukemia,68multiple
myeloma,69chronic lymphocytic leukemia,70and small cell lung cancer.71ABT-263, an
orally bioavailable form of ABT-737, exhibited similar preclinical activity,72and has now
entered clinical trials as a single agent or in combination with other anticancer drugs. Not
surprisingly, given that ABT-737 does not bind to Mcl-1, resistance to ABT-737 has been
associated with Mcl-1, as well as Bfl-1, up-regulation,73indicating that combinatorial
treatment with anticancer agents that target Mcl-174or Bfl-1 could be therapeutically
beneficial. Alternate chemical approaches to generating BH3-mimetics to promote apoptosis
in cancer cells are also producing encouraging results in the preclinical setting.39Thus,
deciphering the mechanisms of apoptosis regulation in tumor cells is yielding novel
opportunities for rational drug design and therapeutic intervention. These analyses can help
predict which tumors have the potential to respond to apoptosis modulation and the types of
drug combinations they may respond to.
Killing the Unkillable Cells: Alternate Approaches to Achieving Tumor Cell
Death
An apoptotic response to therapy in tumors may not always be possible to achieve;
therefore, it is important to determine alternate cell death processes and how to access them
specifically in tumor cells. One intrinsic difference between normal and tumor cells is their
altered metabolism and prevalence of aerobic glycolysis, which is an inefficient means for
generation of adenosine triphosphate (ATP) required for sustaining homeostasis but an
efficient means to generate synthetic precursors to support cell proliferation.75,76This
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tumor cell-specific altered metabolism can provide novel approaches to therapeutically target
cancer but not normal cells.75Altered tumor cell metabolism is frequently coupled with high
energy demand due to a rapid cell growth, with the potential to render tumor cells
susceptible to cell death because of metabolic catastrophe where cellular energy
consumption exceeds production.77
The means to specifically drive tumor cells toward metabolic catastrophe is through
therapeutic nutrient deprivation that may be an additional consequence of the use of
angiogenesis, growth factor, nutrient transporter, and metabolic pathway inhibitors. In
addition, inhibition of the catabolic process of autophagy may similarly create metabolic
deprivation and promote tumor cell death. Importantly, induction of cell death by interfering
with metabolism can occur independently of an intact apoptotic response, suggesting that
modulation of tumor cell metabolism may be therapeutically advantageous.
Autophagy
Role of Autophagy in Promoting Cell Survival to Metabolic Stress
Autophagy is an evolutionarily conserved, stress-activated catabolic lysosomal pathway that
results in degradation of long-lived proteins and organelles. This process involves formation
of the autophagosome, a double-membrane vesicle in the cytosol that engulfs organelles
and cytoplasm and then fuses with the lysosome to form the autolysosome, where the
sequestered contents are degraded and recycled to generate building blocks for
macromolecular synthesis and maintenance of energy homeostasis.78,79Hence the name
autophagy (commonly pronounced aw-tof-je), a term coined from the Greek autoor
oneself, andphagyor eating, accurately depicts the process. Although autophagy can
potentially induce cell death through progressive cellular consumption (autophagy is
sometime referred to as type II programmed cell death), physiologic conditions in mammals
where this occurs have not yet been identified. In most settings, autophagy is a survival
pathway that can delay apoptosis, support metabolism in nutrient stress, and mitigate
cellular damage by preventing the accumulation of damaged proteins and organelles. In
tumor cells with defects in apoptosis, it has recently become apparent that autophagy
supports long-term survival of tumor cells,80,81newly revealing opportunities to target not
only apoptosis, but also the mechanism by which cells survive once apoptosis is disabled.82
Autophagy is regulated by mTOR in the PI3-kinase/AKT pathway that functions to link
nutrient availability to cellular metabolism.83Under conditions of nutrient limitation, normal
cells use this pathway to turn down growth and protein synthesis while activating the
catabolic process of autophagy to maintain energy and biosynthetic homeostasis.79Thus,
autophagy is a temporary survival mechanism during starvation, as self-digestion provides
an alternative energy source.80,8486
On growth factor deprivation, hematopoietic cells activate autophagy, which is essential for
maintenance of ATP production and cellular survival.81In normal mouse development,
amino acid production by autophagic degradation of self proteins allows maintenance of
energy homeostasis and survival during neonatal starvation.87Chronically ischemic
myocardium induces autophagy, which inhibits apoptosis and may function as a
cardioprotective mechanism.88These and other examples indicate that autophagy is
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essential for the maintenance of cellular energy homeostasis that enables survival
particularly during stress and starvation.
Autophagy is not only involved in recycling of normal cellular constituents to support cellular
metabolism, but is also essential for the removal of toxic-damaged proteins and organelles.
The importance of this toxic garbage disposal mechanism is exemplified by the observation
that defects in autophagy result in the accumulation of ubiquitin-positive and p62-positive
protein aggregates, abnormal mitochondria, and deformed cellular structures associated with
production of reactive oxygen species and cellular degeneration.8993This protein and
organelle quality control function of autophagy is important in preserving cellular health and
viability in conjunction with metabolic support via catabolism.
Autophagy also contributes to innate immunity by protecting cells against infection with
intracellular pathogens9497and to acquired immunity by promoting T-lymphocyte survival
and proliferation98and by affecting antigen presentation in dendritic cells and bacterial
handling.99Moreover, autophagy is involved in cellular development and
differentiation,100,101and may have a protective role against aging and age-related
pathologies.102,103
Progressive autophagy can potentially lead to cell death in limited circumstances when
allowed to proceed to completion, and when cells unable to undergo apoptosis are triggered
to die. Unfortunately, it is often unclear whether autophagy is directly involved in initiation
and/or execution of cell death or if it merely represents a failed or exhausted attempt to
preserve cell viability.104Recent studies indicate that autophagy may play an active role in
programmed cell death, but the conditions under which autophagy promotes cell death
versus cell survival remain to be resolved.105108
Role of Autophagy in Tumorigenesis
Defective autophagy has been implicated in tumorigenesis, as the essential autophagy
regulator becn1is monoallelically deleted in human breast, ovarian, and prostate
cancers109and some human breast cancers have decreased Beclin1 levels.110Becn1is the
mammalian orthologue of the yeast atg6/vps30gene, which is required for autophagosome
formation.111Becn1complements the autophagy defect present in atg6/vps30-disrupted
yeast and in human MCF7 breast cancer cells, the latter in association with inhibition of
MCF7-induced tumorigenesis in nude mice.110Becn1/mice die early in embryogenesis,
whereas aging Becn1+/mice have increased incidence of lymphoma and carcinomas of the
lung and liver112,113In addition, mammary tissue from Becn1+/mice shows
hyperproliferative, preneoplastic changes.113Tumors forming in Becn1+/mice express wild
type Beclin1 mRNA and protein, indicating that Becn1is a haploinsufficient tumor
suppressor.112
Recent studies revealed that autophagy enables tumor cell survival in vitroand in vivothat is
particularly obvious in tumor cells when apoptosis is inactivated.80,85,86When angiogenesis
is insufficient, autophagy localizes to the resulting hypoxic tumor regions where it supports
tumor cell viability (Fig.7.8).80,85,86This process of autophagy during nutrient deprivation
allows recovery of growth and proliferative capacity with remarkably high fidelity when
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nutrients, oxygen, and growth factors are restored. Thus, autophagy may be a fundamental
obstacle to tumor eradication.80
Figure 7.8. Role of autophagy in enabling survival of tumor cells to metabolic
stress.
As epithelial tumor cells proliferate and multiple cell layers accumulate, the initial absence of
a blood supply produces metabolic stress in regions most distal to the supply of nutrients
and oxygen often in the center of the tumor mass. In tumor cells with apoptosis defects, this
allows tumor cells in these metabolically stressed tumor regions to survive through
autophagy. Subsequent angiogenesis relieves metabolic stress, obviating the need for
autophagy, fueling tumor growth.
How inactivation of a survival pathway promotes tumorigenesis has been an intriguing
question. The apparently conflicting pro-survival and pro-death functions of autophagy can,
however, be reconciled if one considers autophagy a prolonged but interruptible pathway to
cell death on stress and starvation, where nutrient restoration prior to its culmination can
provide cellular salvation. This contrasts the death processes of apoptosis and necrosis,
which are executed rapidly and are irreversible. As such, the identification of the precise
mechanism by which autophagy supports survival is critical.
Autophagy not only provides an alternate means for energy generation during periods of
starvation, but also has a role in cellular damage mitigation through promotion of protein
and organelle quality control, especially under conditions of stress in which proteins and
organelles become damaged. By degrading damaged proteins and organelles, autophagy
prevents their accumulation, which can be toxic. This function of autophagy is particularly
critical in stressed tissues and tumors, which are regularly subjected to metabolic stress by
their dependence on the inefficient process of aerobic glycolysis and by their intermittently
limited blood supply during rapid tumor growth or metastasis. Thus, autophagy defects in
tissues and tumors reduce cellular fitness and render cells prone to DNA damage, mutation,
and genomic instability,85,86,92which in turn contribute to tumor initiation and
progression.82,114,115
In addition to these cell-autonomous mechanisms, defective autophagy can promote
tumorigenesis in a noncell-autonomous way by reducing tumor cell survival that causes
chronic cell death and inflammation in tumors.80,92,115Autophagy can thereby be thought
of as a double-edged sword. On the one hand, autophagy promotes tumor cell survival
through maintaining energy homeostasis and mitigating oxidative damage by preventing the
accumulation of aggregated proteins and abnormal organelles. On the other hand, defects in
autophagy elevate oxidative stress, DNA damage, and mutation, and promote chronic cell
death and inflammation, all of which are linked to promotion of cancer initiation and
progression.115These observations have led to the notions that autophagy stimulation can
prevent cancer, whereas inhibiting autophagy-mediated survival is an approach to treatingestablished, aggressive cancers.82,114
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Autophagy Modulation for Cancer Treatment
As autophagy can enable tumor cell survival to stress,80,81the means to block autophagy
has the potential to promote cell death that may be therapeutically
advantageous.82,114Moreover, both targeted and cytotoxic antineoplastic agents have been
observed to induce autophagy in human cancer cell lines,116,117possibly as a survivalmechanism in response to treatment-induced stress. Thus, autophagy inhibitors are
expected to deprive cancer cells of an essential survival mechanism and consequently render
them more susceptible to cell death. This novel paradigm in cancer therapy has been
validated in several preclinical studies.118126This approach is now under investigation in
phase 1/2 clinical trials involving autophagy inhibition by the antimalarial drug
hydroxychloroquine, which blocks lysosome degradation of the products of autophagy, in
combination with standard chemotherapy.
Necrosis
Recent evidence suggests that tumor cells in which apoptosis has been disabled can be
diverted to necrosis, which has traditionally been considered an unregulated (and thus, not
programmed) form of cell death implicated in pathologic states, such as ischemia, trauma,
and infection.127Recent evidence is calling the unregulated nature of necrosis into question.
Necrosis is derived from the Greek word nekrosfor corpse, and it involves rapid swelling of
the cell, loss of plasma membrane integrity, and release of the cellular contents into the
extracellular environment, resulting in an acute inflammatory response. Necrosis is largely
viewed as an accidental and unregulated cellular event triggered by cellular trauma (direct
physical injury), acute energy depletion, or extreme stress.128Recently, a type of
programmed necrotic cell death, called necroptosis,129has been identified as induced by
interaction of death domain receptors with their respective ligands under conditions of
defective or inhibited downstream apoptotic machinery.130Necroptosis depends on the
serine/threonine kinase activity of the death domain receptor-associated adaptor Rip1 and its
relative Rip3.131136Necroptosis is potently inhibited by the Rip1 kinase inhibitors, the
necrostatins.133In a genome-wide siRNA screen for necroptosis regulators, a set of 432
genes with enriched expression in the immune and nervous systems was identified and
cellular sensitivity to necroptosis was found to depend on the same signaling network that
mediates innate immunity.131Harnessing necroptosis to induce cell death in cancer is an
exciting new prospect, the exploitation of which will require a deeper mechanistic insight intothe process and its regulation.
Regarding necrosis as a therapeutic end point, tumor cell fate in response to treatment with
DNA-damaging agents depends on the effect of the DNA repair protein poly(ADP-ribose)
polymerase (PARP) on cellular metabolism. PARP activation by DNA-damaging alkylating
agents causes PARP-mediated -nicotinamide adenine dinucleotide (NAD) consumption, ATP
depletion, and metabolic stress. The glycolytic state (Warburg effect) and inefficient mode of
energy production in most cancer cells renders them sensitive to this ATP depletion in
response to PARP activation, resulting in induction of necrotic cell death of apoptosis-
defective tumor cells.137Tumor cells with defects in both apoptosis and autophagy may be
particularly susceptible to death by necrosis as loss of autophagy potential deprives cells of
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an alternate energy source for maintenance of metabolism and viability in metabolic stress
that is compounded by the Warburg effect.80
Manipulation of tumor cell metabolism is an appealing therapeutic approach, as it can be
used to induce cancer cell death by metabolic catastrophe.77This is particularly relevant for
tumors with increased proliferative capacity and high bioenergetic requirements, such as
tumors with constitutive activation of the PI3-kinase/Akt pathway, which are unable to
down-regulate metabolism and to activate autophagy in response to starvation. Thus, the
very properties that confer cancer cells with the capacity for rapid growth may also render
them susceptible to metabolic stress pharmacologically induced by a wide variety of means,
including nutrient deprivation, angiogenesis inhibition, glycolysis inhibition, accelerated ATP
consumption, or autophagy inhibition. Furthermore, necrotic cell death can be genetically
determined indirectly through manipulation of cellular bioenergetics (decreased energy
production through autophagy and catabolism inhibition, increased metabolic demand
through elevated consumption, or decreased nutrient availability) or directly by activatingRip kinases or PARP. It will be of great interest to see if necrosis, like apoptosis, can be
exploited for cancer therapy.
It is becoming clear that cells possess multiple death mechanism, and establishing how these
are altered in tumors and can be activated with therapy is essential. Defining at the
molecular level how apoptosis is regulated has led to the development of novel cancer
therapies aimed at triggering or restoring apoptotic function in tumor cells, and this progress
is likely to continue. Moreover, defining the mechanisms by which common mutations in
human tumors inactivate apoptosis has yielded novel opportunities for tumor-genotype
specific rational chemotherapy targeting the apoptotic pathway. In tumor cells whereapoptosis is disabled, it is apparent that alternate forms of cell death can be activated,
including necrosis, the process by which remains poorly characterized. Finally, the catabolic
process of autophagy can promote tumor cell survival to metabolic stress, providing new
opportunities for therapeutic intervention, in part capitalizing on the altered metabolic state
intrinsic to tumor cells.
References
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6. Morgenbesser SD, Williams BO, Jacks T, DePinho RA. p53-dependent apoptosisproduced by Rb-deficiency in the developing mouse
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