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Chapter 18 Cell Death 195

support the notion that autophagy is primarily a self-limiting survival survival pathway. In addition, recruitment of the adaptor protein
pathway and a temporary adaptive response during metabolic stress, TRAF2 to IRE1 may further sensitize cells to ER-stress mediated
which can promote cell death if not terminated. apoptosis through activation of ER-linked caspases or c-Jun-terminal
The interrelationship among apoptosis, autophagy, and necrosis kinase.
carries significant relevance in tumor settings where defects in the Emerging evidence from multiple experimental systems indicates
apoptotic pathway (e.g., overexpression of BCL-2 or BAX, or BAK that select protein modulators of UPR can be both prosurvival or
deficiency) and abnormal upregulation of proliferation (e.g., consti- prodeath depending on the extent of ER damage or the duration
tutive activation of the PI3K/AKT pathway) are common. Prior to of UPR. The discovery of BAX and BAK association with IRE1
vascularization, malignant cells in the center of tumors are exposed to and modulation of its downstream effectors, such as XBP1, suggest
14
hypoxia and metabolic stress. Here, autophagy meets the bioenergetic cross-talk between BCL-2 family proteins and UPR. Interestingly,
demands of tumor cells until vascularization supplies oxygen and the role of BAX and BAK in UPR is distinct from their function at
nutrients. When exposed to hypoxia and nutrient limitation, such mitochondria. How BAX and BAK modulate IRE1 activity/signaling
apoptosis-resistant tumor cells cannot undergo autophagy due to and whether they execute a direct role or an accessory function during
constitutive activation of AKT. They revert instead to necrosis, which each of the adaptive/protective or apoptotic phases of UPR and ER
through inflammation and stimulation of cytokine and chemokine stress remain to be determined.
production has been proposed to initiate a cellular repair program
analogous to wound healing, further promoting proliferation and
angiogenesis. Indeed, necrotic tumors are known to have poor Oncogene-Induced Apoptosis
prognosis. The above findings also explain, in part, why defects
in autophagy are tumorigenic despite the notion that autophagy is Hyperactivity of mitogenic oncogenes such as Myc, adenovirus
primarily a survival pathway during metabolic stress. E1A, and Ras triggers a common pathway of p53 accumulation
via stabilization of the ARF tumor suppressor protein. p14ARF (or
p19ARF in mice) is encoded by an alternative reading frame in the
Unfolded Protein Response p16INK4a locus. ARF inhibits Mdm2, the p53 E3 ubiquitin ligase,
and also exhibits p53-independent functions, including binding to
Protein stress responses also link into apoptotic pathways. These Myc and E2F transcription factors, inhibiting transactivation of
highly conserved mechanisms provide feedback fidelity control of target genes. The nature of the oncogenic stress leading to induction
protein folding, glycosylation, and secretory pathways in the ER of ARF is still poorly understood, but may involve DNA replication
and other subcellular compartments. Multiple inputs (amino acid or nucleolar stress.
deficiency, glucose deprivation, calcium dysregulation, redox poise)
trigger this pathway via their effects on ER protein folding.
Three protein sensors, protein kinase-like ER kinase or EIF2AK3 CLINICAL APPLICATIONS
(PERK), activating transcription factor 6 (ATF6), and inositol requir-
ing transmembrane kinase/endonuclease 1 or ERN1 (IRE1), are Abnormal regulation of cell death pathways is believed to contribute
triggered in response to unfolded proteins within the ER, and activate significantly to several diseases associated with excess cell number
a homeostatic process that reduces production of new client proteins or function (e.g., neoplasia, autoimmune disorders) or accelerated
for the ER folding machinery, helps refold misfolded proteins, and cell loss (marrow failure syndromes, neurodegenerative diseases). The
degrades protein aggregates. 14,24 The activity of these sensors is clearest supporting evidence is linkage to an altered gene sequence
normally held dormant due to association with the ER chaperone or epigenetic alteration, followed by mechanism testing in cellular/
BiP (HSPA5). During the unfolded protein response (UPR), BiP is animal models. As previously discussed, BCL-2 gene rearrangement
bound and sequestered by unfolded proteins, leading to derepres- is associated with t(14;18) in follicular B-cell lymphomas, leading to
sion of each UPR sensor. PERK is activated by dimerization and transcriptional activation and high expression levels. Mutations in the
autophosphorylation to subsequently phosphorylate the translation Bax coding region are found in approximately 50% of colorectal and
initiation factor eIF2α, leading to inhibition of general protein trans- gastric cancers associated with mismatch repair defects, representing
lation and selective increase in ATF4 translation. The transcription frame-shift mutations at a poly(G)8 tract in the coding region.
factor ATF4, in turn, increases the expression of select chaperones One of the anticipated benefits of basic research on cell death
and antioxidant defense genes. ATF6 is activated upon translocation pathways is the ability to selectively manipulate cell survival or cell
to the Golgi and undergoes subsequent proteolytic cleavage to a death through rational drug design. Members of the BCL-2 protein
fragment that translocates to the nucleus and binds the UPR response family, p53, and caspases have been targets of intensive efforts at drug
element found in the promoters of target genes. Another UPR sensor, discovery and design. Two small-molecule inhibitors of BCL-2 and
the bifunctional protein kinase IRE1, is activated by dimerization and related antiapoptotic proteins (BCL-X L and MCL-1) have advanced to
transphosphorylation, leading to stimulation of its inherent endori- phase I–II clinical trials for chronic lymphocytic leukemia, Hodgkin
bonuclease activity and processing of mRNA encoding the basic and non-Hodgkin lymphoma, acute myelogenous leukemia, multiple
leucine zipper transcription factor X-box binding protein 1 (XBP1). myeloma, and myelofibrosis. 25,26 These and several other inhibitors
XBP1, together with ATF6, regulates transcription of additional genes in late preclinical development bind to the hydrophobic groove in a
required for UPR, including chaperones, folding enzymes, protein similar manner to proapoptotic BH3 peptides, and are understood to
disulfide isomerase, ER-associated degradation components, and act by preventing antiapoptotic proteins from sequestering proapop-
autophagy genes. Increased ER-associated degradation components totic proteins in the BCL-2 family. In addition, a broad-spectrum
and autophagy help clear unfolded proteins, protein aggregates, and oxamyl dipeptide caspase inhibitor has completed phase II trials in
damaged organelles. Increased ER biogenesis is also part of the UPR treatment-resistant hepatitis C and orthotopic liver transplantation. 27
transcriptional program ensuring sufficient ER mass matches the As targeted drugs against individual members of the BCL-2
protein quality control response. This process is especially important antiapoptotic protein family enter clinical trials, a rapid and accurate
for the differentiation of B-lymphocytes to antibody-secreting plasma cellular assay known as BH3 profiling has been developed to predict
cells. If the integrated outcome of these signaling pathways does not their efficacy in primary cancer cells. 28
salvage the ER load of unfolded and aggregated proteins, these same
UPR sensors can engage the intrinsic pathway of apoptosis. 14,24 TP53
and CHOP/GADD153, a transcription factor induced by ATF4, SUMMARY
initiate an ER stress-associated transcription program that is marked
by changes in expression levels of several BCL-2 family members, Apoptosis is an evolutionarily conserved, highly regulated mechanism
death receptors such as Fas and DR5, and attenuation of the AKT for maintaining cell and tissue homeostasis in multicellular organisms.