chapter 7 - mechanisms of cell death

8/13/2019 Chapter 7 - Mechanisms of Cell Death

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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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2. Wyllie AH, Kerr JF, Currie AR. Cell death: the significance of apoptosis. Int RevCytol1980;68:251.[PMID: 7014501]

3. Rao L, Debbas M, Sabbatini P, Hockenbery D, Korsmeyer S, White E. The adenovirusE1A proteins induce apoptosis, which is inhibited by the E1B 19-kDa and Bcl-2

proteins. Proc Natl Acad Sci U S A1992;89:7742.[PMID: 1457005]

4. Fanidi A, Harrington EA, Evan GI. Cooperative interaction between c-myc and bcl-2proto-oncogenes. Nature1992;359:554.[PMID: 1406976]

5. Evan GI, Wyllie AH, Gilbert CS, et al. Induction of apoptosis in fibroblasts by c-mycprotein. Cell1992;69:119.[PMID: 1555236]
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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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chapter 7 - mechanisms of cell death

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