Apoptosis, Senescence and Cancer (eBook)

Preface 6
Contents 7
Contributors 10
CELL DEATH PATHWAYS 13
SENESCENCE GROWTH ARREST 14
DRUGS, MECHANISMS, AND RESISTANCE 14
DNA DAMAGE RESPONSE 14
UNANSWERED QUESTIONS 15
The Intrinsic Pathway of Apoptosis 17
1. ANTICANCER DRUGS CAN INDUCE APOPTOSIS 17
2. CASPASE ACTIVATION: SHARPENING THE SCALPEL 18
3. CLEAVAGE BY EFFECTOR PROTEASES: SURGICAL EXCISION OF CRITICAL CELLULAR COMPONENTS 19
4. CYTOCHROME C: A CRITICAL MOLECULE FOR LIFE AND DEATH 19
5. BCL-2 FAMILY MEMBERS AND THE INTEGRATION OF CELLULAR STRESS 21
6. GROUP III FAMILY MEMBERS: ARMING THE ASSASSIN 23
7. GROUP I POLYPEPTIDES: KEEPING THE KILLERS IN CHECK 24
8. CASPASE INHIBITION BY XIAP: CLOSING THE BARN DOOR AFTER THE COW HAS ESCAPED 25
9. ADDITIONAL PROAPOPTOTIC MITOCHONDRIAL PEPTIDES: THE EXECUTIONER’S ARSENAL 27
10. ACTIVATION OF THE APOPTOTIC MACHINERY BY CHEMOTHERAPEUTIC AGENTS 28
12. ARE ALTERATIONS IN THE APOPTOTIC MACHINERY 31
11. LIFE ON THE EDGE: ALTERATIONS IN THE APOPTOTIC MACHINERY IN CANCER CELLS 30
13. CONCLUSIONS 33
ACKNOWLEDGMENTS 33
REFERENCES 33
The Extrinsic Pathway of Apoptosis 45
1. OVERVIEW OF SIGNALING EVENTS 45
2. ROLE OF THE EXTRINSIC PATHWAY IN DISEASE 52
3. ROLE OF EXTRINSIC PATHWAY IN CHEMOTHERAPY AND RADIOSENSITIVITY 56
4. EXPLOITING THE EXTRINSIC PATHWAY FOR CHEMOTHERAPY-INDUCED KILLING 57
5. CONCLUDING REMARKS 60
REFERENCES 61
Evaluating the Importance of Apoptosis and Other Determinants of Cell Death and Survival 69
1. INTRODUCTION 69
2. FORMS OF CELL DEATH 70
3. INVOLVEMENT OF CELL DEATH DURING TUMOR DEVELOPMENT AND TREATMENT 74
4. CONSIDERATION OF CELL DEATH KINETICS AND DOSE RESPONSES IN RELATION TO SURVIVAL 75
5. LABORATORY EVALUATION OF TREATMENT RESPONSES AND THEIR INTERPRETATIONS 77
6. CONCLUSIONS 82
REFERENCES 83
Mitotic Catastrophe 87
1. MOLECULAR MECHANISMS UNDERLYING MITOTIC CATASTROPHE 87
2. STRESS-INDUCED MC 92
3. DELAYED DNA DAMAGE ASSOCIATED WITH MC 94
4. PROMOTING MC MAY ADVANTAGEOUSLY INCREASE CLINICAL OUTCOME 97
5. MC AND TUMOR PROGRESSION 98
6. CONCLUDING REMARKS 100
REFERENCES 100
Autophagy and Autophagic Cell Death 106
1. INTRODUCTION 106
2. MOLECULAR CONTROL OF AUTOPHAGY 107
3. REGULATION AND SIGNALING OF AUTOPHAGY 109
4. AUTOPHAGY IN CANCER CELLS 110
5. AUTOPHAGIC CELL DEATH 112
6. CONCLUSION 114
ACKNOWLEDGMENTS 115
REFERENCES 115
Regulation and Function of Detachment-Induced Cell Death (Anoikis) in Cancer Progression and Metastasis 121
1. SOCIAL CONTROLS ON CELL SURVIVAL AND CELL DEATH 121
2. ADHESION-DEPENDENT SURVIVAL SIGNALING 122
3. MOLECULAR MECHANISMS UNDERLYING DETACHMENT-INDUCED APOPTOSIS 124
REFERENCES 130
Structure and Function of the Telomere 136
1. INTRODUCTION 136
2. HISTORICAL PERSPECTIVE 137
3. THE PRIMARY STRUCTURE OF TELOMERIC DNA 138
4. THE SECONDARY STRUCTURE OF TELOMERIC DNA 140
5. TELOMERIC PROTEINS AND THE TELOSOME 141
6. TELOMERASE 146
7. REGULATION OF TELOMERASE ACTIVITY 146
8. ALTERNATIVE LENGTHENING OF TELOMERES 148
9. CELLULAR IMPLICATIONS OF TELOMERE DYSFUNCTION 149
10. THE ROLES OF TELOMERASE ACTIVATION IN GENETIC INSTABILITY AND TUMOR PROGRESSION 150
11. CONCLUDING REMARKS 151
ACKNOWLEDGMENTS 151
REFERENCES 151
Overview of Senescence 156
1. CELLULAR SENESCENCE 156
2. REPLICATIVE SENESCENCE 157
3. STRESS-INDUCED SENESCENCE 161
4. CONCLUSION 163
REFERENCES 164
Contributions of Telomerase to Tumorigenesis 169
1. INTRODUCTION 169
2. TELOMERE STRUCTURE 170
3. TELOMERES AND CELL MORTALITY 171
4. TELOMERES, DNA DAMAGE, AND REPLICATIVE LIFESPAN 173
5. THE TELOMERE AND CANCER 174
6. ALTERNATIVE FUNCTIONS OF TELOMERASE 175
7. TELOMERE-BASED THERAPIES AND THERAPEUTIC 176
CONSIDERATIONS 176
REFERENCES 177
The Role of Telomeres in Genomic Instability 182
1. GENOMIC INSTABILITY AND CANCER 183
2. STRESS-INDUCED GENOMIC INSTABILITY 183
3. TELOMERE STRUCTURE AND FUNCTION 184
4. MECHANISMS AND CONSEQUENCES OF TELOMERE LOSS 185
5. TELOMERE LOSS AND CANCER 188
6. MECHANISMS OF RESTORATION OF LOST TELOMERES 189
7. THE USE OF SELECTABLE MARKER GENES TO MONITOR THE CONSEQUENCES OF TELOMERE LOSS 190
ACKNOWLEDGMENTS 193
REFERENCES 193
Overview of the DNA Damage Checkpoint 200
1. INTRODUCTION 200
2. BIOCHEMISTRY OF ATM AND ATR 206
3. FUNCTIONS OF ATM AND ATR 213
4. CONCLUSIONS 220
REFERENCES 221
Interactions Between Myc- and Cyclin-Dependent Kinase Inhibitors in Cancer 229
1. INTRODUCTION 229
2. MYC’S TRANSCRIPTION FUNCTIONS 230
3. MYC AND GROWTH CONTROL 231
4. INK4 AND CIP/KIP CDK INHIBITORS IN CELL-CYCLE CONTROL 232
5. LOSS OF INK4/CDK INHIBITORS IN CANCER 235
6. REGULATORY CIRCUITS BETWEEN MYC AND CKIS 237
REFERENCES 239
Interplay Between H2AX and 53BP1 Pathways in DNA Double-Strand Break Repair Response 248
1. GENERAL CHARACTERISTICS OF DOUBLE-STRAND BREAK DAMAGE RESPONSE NETWORKS 248
2. CHROMATIN-BASED EVENTS IN RESPONSE TO DSBs 250
3. INTERPLAY BETWEEN H2AX AND 53BP1 261
4. OPEN QUESTIONS AND PERSPECTIVES 264
REFERENCES 265
DNA-Dependent Protein Kinase in Repair, Apoptosis, Telomere Maintenance, and Chemotherapy 269
1. BIOCHEMICAL PROPERTIES OF DNA-DEPENDENT PROTEIN KINASE 269
2. DIRECT ROLE IN DNA DSB REPAIR 271
3. DNA-PK AND APOPTOSIS 273
4. DNA-PK, TELOMERES, AND SENESCENCE 275
5. DNA-PK AND CHEMOTHERAPY/RADIOTHERAPY 276
ACKNOWLEDGMENTS 277
REFERENCES 277
Resistance/Signaling Pathways 284
1. SELF-LIMITING EFFECTS OF CANCER THERAPIES: AGENTS THAT CAUSE INCOMPLETE KILLING AND THE COMPENSATORY ACTIVATION OF GROWTH FACTOR RECEPTORS AND SURVIVAL SIGNALING PATHWAYS 285
2. A PARADIGM FOR DOWNSTREAM PROTECTIVE PATHWAYS: THE “CLASSICAL” MITOGEN-ACTIVATED PROTEIN KINASE PATHWAY, ERK1/2 286
3. DOWNSTREAM PROTECTIVE PATHWAYS: PI3K/AKT SIGNALING AND THE INTERACTIONS OF PI3K/AKT SIGNALING WITH RAF/ERK1/2 PATHWAY SIGNALING 288
4. DOWNSTREAM CYTOTOXIC PATHWAYS: THE C-JUN KINASE AND STRESS-ACTIVATED PATHWAY, JNK1/2/3 290
5. A SIMPLISTIC SCENARIO FOR CELL SURVIVAL SIGNALING AFTER EXPOSURE TO A NOXIOUS STRESS: INHIBITION OF RAF/MEK/ERK1/2 FUNCTION AND/OR PI3K/AKT FUNCTION TO CIRCUMVENT PROTECTIVE SIGNALING PROCESSES INDUCED BY CYTOTOXIC INSULTS THUS PROMOTES DRUG/RADIATI 291
6. CONCLUSIONS 293
ACKNOWLEDGMENTS 293
REFERENCES 293
Ceramide and Multidrug Resistance 302
1. INTRODUCTION 302
2. CERAMIDE IN GROWTH ARREST AND CELLULAR SENESCENCE 303
3. CERAMIDE SIGNALING PATHWAYS 304
4. CERAMIDE GENERATION BY CHEMOTHERAPEUTIC AGENTS 304
5. DRUG RESISTANCE IN CANCER 305
6. GCS AND CELLULAR RESPONSE TO CHEMOTHERAPY 305
7. INFLUENCE OF CERAMIDE ON MULTIDRUG RESISTANCE 307
8. GCS AND THE MDR1 PHENOTYPE 308
9. CONCLUSIONS 309
ACKNOWLEDGMENTS 310
REFERENCES 310
Chemo- and Radiosensitization Through Inhibition of PI3K/Akt Signaling 316
1. INTRODUCTION 316
2. PI3K/AKT SIGNALING IN CELL BIOLOGY 318
3. DYSREGULATION OF PI3K/AKT SIGNALING IN CANCER 321
4. CANCER THERAPEUTICS TARGETING PI3K/AKT SIGNALING 325
5. CONCLUSION 330
ACKNOWLEDGMENT 331
REFERENCES 331
The Advancement of Epidermal Growth Factor Receptor Inhibitors in Cancer Therapy 338
1. INTRODUCTION 338
2. EGFR STRUCTURE AND FUNCTION 339
3. EGFR—SIGNIFICANCE IN ONCOLOGY 342
4. PRECLINICAL STUDIES 344
5. CLINICAL STUDIES 348
6. CONCLUSION 352
REFERENCES 353
Antimetabolites 362
1. PROGRAMMED CELL DEATH 363
2. PASSIVE (NECROSIS) CELL DEATH 372
3. SENESCENCE ARREST AND DIFFERENTIATION 372
4. CONCLUSIONS 373
ACKNOWLEDGMENTS 373
REFERENCES 373
Topoisomerase I Poisons and Apoptotic Topoisomerase I-DNA Complexes 384
1. INTRODUCTION 384
2. NOVEL TOPOISOMERASE I POISONS 386
3. MOLECULAR MODEL FOR TOPOISOMERASE I INHIBITION: MISALIGNMENT OF THE 5 -HYDROXYL END OF THE CLEAVED DNA AND INTERFACIAL INHIBITION 389
4. CELLULAR LESIONS INDUCED BY TOPOISOMERASE I POISONS 391
5. SENSING DNA DAMAGE INDUCED BY TOPOISOMERASE I POISONS: ATM, ATR AND DNA-PK 391
6. MITOCHONDRIAL AND PLASMA MEMBRANE RECEPTOR PATHWAYS ARE ACTIVATED BY TOPOISOMERASE I POISONS 392
7. FROM DNA DAMAGE IN THE NUCLEUS TO APOPTOSIS IN THE CYTOPLASM 394
8. FORMATION OF TOP1 CLEAVAGE COMPLEXES DURING APOPTOSIS 398
9. CONCLUSION 399
ACKNOWLEDGMENT 400
REFERENCES 400
Perturbations of Cellular Functions by Topoisomerase II Inhibitors 408
1. DRUG-INDUCED CELL DEATH 408
2. TOPOISOMERASE II AND ITS INHIBITORS 410
3. CELL DEATH AND CELL GROWTH ARREST 412
ACKNOWLEDGMENTS 419
REFERENCES 420
The Significance of Poly-Targeting in Apoptosis Induction by Alkylating Agents and Platinum Drugs 424
1. INTRODUCTION 425
2. TARGETING PROFILES OF AA AND PT DRUGS 429
3. GENERAL ATTRIBUTES OF CELL DEATH INDUCED BY AA AND PT DRUGS 434
4. IS THE TARGETING OF DNA ALONE ALWAYS SUFFICIENT FOR APOPTOSIS BY AA? 435
5. PROTEIN DAMAGE IN CELL DEATH—THE PROTEOME AS A COLLECTIVE APOPTOTIC TARGET 437
6. ENHANCED APOPTOSIS BY COMBINED TARGETING OF DNA AND PROTEIN REDOX STATUS 441
7. CONCLUDING REMARKS 451
ACKNOWLEDGMENTS 453
REFERENCES 453
Contributions of Apoptosis and Senescence to Cytotoxicity Produced by Microtubule-Stabilizing Agents 465
1. INTRODUCTION 466
2. CELL DEATH AFTER MICROTUBULE STABILIZATION 466
3. ACCELERATED SENESCENCE 470
4. CONCLUSION 472
REFERENCES 472
Tyrosine Kinase Inhibitors 477
1. TYROSINE KINASES IN MALIGNANT DISEASE 477
2. DEVELOPMENT OF IMATINIB 483
3. FLT3 INHIBITORS FOR ACUTE MYELOID LEUKEMIA 495
4. DEVELOPMENT OF GEFITINIB AND ERLOTINIB FOR NON-SMALL CELL LUNG CANCER 497
5. PERSPECTIVE 500
ACKNOWLEDGMENTS 501
REFERENCES 501
Monoclonal Antibodies in Lymphomas 510
1. INTRODUCTION 510
2. RITUXIMAB 516
3. ALEMTUZUMAB 522
4. CONCLUSIONS 528
REFERENCES 529
Role of Apoptosis in Anti-Angiogenic Cancer Therapies 536
1. INTRODUCTION: ANGIOGENESIS IN TUMOR GROWTH 536
2. ANGIOGENIC INDUCTION AND THE TUMOR VASCULATURE 538
3. TARGETING THE VASCULATURE IN CANCER THERAPY 539
4. EVIDENCE FOR ENDOTHELIAL CELL APOPTOSIS AS A PRIMARY EVENT IN ANTI-ANGIOGENIC THERAPY 541
5. THE ACTIVATED VEC: PRIMED FOR APOPTOSIS 542
6. APOPTOTIC INDUCTION IN ACTIVATED VECs 544
7. CLINICAL TRIALS: DIRECT AND INDIRECT ANTI-ANGIOGENIC AGENTS 547
8. CONCLUSIONS AND FUTURE POSSIBILITIES 548
REFERENCES 549
Photodynamic Therapy-Induced Apoptosis 555
1. PHOTODYNAMIC THERAPY: AN INTRODUCTION 556
2. CHEMICAL AND BIOCHEMICAL PROPERTIES OF THE PHOTOSENSITIZERS USED IN PDT 558
3. PDT-INDUCED APOPTOSIS 559
4. CELLULAR TARGETS OF PDT: MITOCHONDRIA 560
5. CELLULAR TARGETS OF PDT: LYSOSOMES 565
6. CELLULAR TARGETS OF PDT: ER 566
7. CELLULAR TARGETS OF PDT: PLASMA MEMBRANE 568
8. A MODEL FOR ORGANELLE PARTICIPATION IN APOPTOSIS FOLLOWING PDT 569
ACKNOWLEDGMENTS 570
REFERENCES 570
Modulation of TRAIL Signaling for Cancer Therapy 577
1. INTRODUCTION 577
2. THE CORE APOPTOTIC MACHINERY 578
3. TRAIL AND ITS RECEPTORS 579
4. TRAIL SIGNALING 579
5. DEFECTIVE TRAIL SIGNALING IN CANCERS 579
6. TRAIL AND CANCER THERAPY 581
7. CONCLUSIONS 584
REFERENCES 584

5 Autophagy and Autophagic Cell Death (p. 92-93)

Mojgan Djavaheri-Mergny PhD,
Joëlle Botti PhD, and Patrice Codogno PhD

Summary

Macroautophagy or autophagy is a degradative pathway terminating in the lysosomal compartment after the formation of a cytoplasmic vacuole that engulfs macromolecules and organelles. During the last decade, progress made in our understanding of the molecular controls of autophagy has uncovered the importance of tumor suppressor molecules in the stimulation of autophagy. Downexpression of autophagy is an early event during tumorigenesis. However, the relation between autophagy and tumor progression seems to be more complex because cancer cells are able to trigger autophagy in response to various situations including changes in their extracellular environment and cancer treatments. The role of autophagy in cancer cells balances between two apparently opposite outcomes. Autophagy as a stress response mechanism can protect cancer cells from various insults. But autophagy can eliminate cancer cells by triggering autophagic cell death. These two aspects of autophagy will be discussed in this review.

Key Words: Autophagy, apoptosis, cell death, cancer, macroautophagy, lysosome, signal transduction.

1. INTRODUCTION

Autophagy is a lysosomal degradative mechanism occurring in different modes (chaperone-mediated autophagy, microautophagy, and macroautophagy) (1). This chapter is dedicated to macroautophagy (hereafter referred as to autophagy). Autophagy is a general and evolutionarily conserved vacuolar catabolic pathway terminating in the lysosomal compartment (2–4). It contributes to the quality control of cytoplasmic components by recycling macromolecules (autophagy is responsible for the turnover of long-lived proteins) and removing organelles when damaged or in excess (peroxisomes, mitochondria). From a cell biology standpoint, autophagy is characterized by the formation of a multimembrane-bound autophagosome that engulfs portions of the cytoplasm. The delimiting membrane of the autophagosome is derived from an ‘isolation’ membrane or phagophore of unknown origin (5). In mammalian cells, most autophagosomes can fuse directly with lysosomes or merge with endocytic compartments (6,7) to form an amphisome where the sequestered material is denatured because of the acidic environment. The final step is the fusion of amphisomes with the lysosomal compartment where the sequestered material is degraded.

The discovery of autophagy by de Duve and Wattiaux (8) was contemporary with that of lysosomes. The physiological importance of autophagy in maintaining cell homeostasis in organs such as liver and in cultured cells rapidly emerged (9,10). At the same time, the term autophagic cell death or type II programmed cell death (PCD II) was introduced to describe a cell death different from apoptosis or type I PCD (PCD I) (11,12). From these data, it appeared that autophagy is a cell response to stress, which under certain circumstances can lead to cell death. However, the precise role of autophagy as a cell death mechanism remains to be explored (13). Identification of its molecular machinery and signaling pathways has shed some light on the importance of autophagy in physiological processes and diseases (1,2,14). Among the autophagy-related (ATG) genes, discovered in yeast and almost integrally conserved in all eukaryotic phyla, which control the formation of the autophagosome (15), beclin 1 (the mammalian ortholog of the yeast ATG6) is a tumor suppressor gene that contributes to a complex with the class III phosphatidylinositol-3- kinase (PI3K) to the formation of the autophagosome (16,17). Other tumor suppressor gene products [p53, PTEN, TSC1/TSC2, death-associated protein kinase (DAP kinase)] are involved in the control of autophagy (18). Interestingly, autophagy is also stimulated in cancer cells by ceramide (19,20), a tumor suppressor lipid (21).