Cellular Respiration and Carcinogenesis (eBook)

Foreword 4
Contents 6
Contributors 8
Oxidative Phosphorylation and Cancer: The Ongoing Warburg Hypothesis 11
The Electron Transport Chain and Carcinogenesis 29
2.1 Introduction 29
2.2 Mitochondria and Cancer: A Long History 30
2.3 The Respiratory Chain: Biochemical and Genetic Features 30
2.4 Mutations in Three Nuclear Genes Encoding Respiratory Chain Complex II Can Promote Tumor Formation 32
2.5 Does a Defective Respiratory Chain Trigger Cell Proliferation? 35
2.6 Mitochondria, Superoxides, Hypoxia 37
2.7 Targeting the Respiratory Chain to Kill Tumors 39
2.8 Conclusion 40
Respiratory Control of Redox Signaling and Cancer 43
3.9 ROS and Redox Signaling 43
3.10 Mitochondrial ROS and Cell Cycle 45
3.11 Mitochondrial ROS and Cell Survival 46
3.12 Mitochondrial ROS and Angiogenesis 47
3.13 Mitochondrial ROS and Invasion/Migration 49
3.14 Mitochondrial ROS and Cancer Stem Cells 51
3.15 Conclusion 52
Cellular Respiration and Dedifferentiation 55
4.16 Introduction 55
4.17 Cellular Respiration and Dedifferentiation 59
4.18 Conclusion 62
Cellular Adaptations to Oxidative Phosphorylation Defects in Cancer 65
5.19 Mammalian Oxidative Phosphorylation 65
5.20 OXPHOS Defects in Cancer 66
2.1 Functional Significance of OXPHOS Defects in Cancer 67
5.21 Cellular Adaptations to OXPHOS Defects in Cancer 69
3.1 Retrograde Signaling in Cancer Cells 70
3.1.1 Altered Expression of OXPHOS Regulatory Genes and Subunits 70
3.1.2 Activation of Genes Involved in Tumor Invasion and Progression 71
3.1.3 Activation of Calcium Signaling Pathway 72
3.1.4 Activation of Redox Signaling Pathway 73
3.1.5 Altered Antioxidant Defense Pathway 75
3.1.6 Altered Mitochondrial Morphology, Cell Surface, and Architecture 75
3.1.7 Activation of Antiapoptotic Genes 76
3.2 Mechanism of Retrograde Signaling 77
5.22 Conclusion 78
5.23 Note 78
Regulation of Glucose and Energy Metabolism in Cancer Cells by Hypoxia Inducible Factor 1 83
6.23 Oxygen Homeostasis 83
6.24 HIF-1 Structure 84
6.25 HIF-1 Regulation 85
6.26 HIF-1 Isoforms 89
6.27 HIF-1 Induction by Nonhypoxic Stimuli 90
6.28 HIF-1 in Cancer 90
6.29 HIF-1, Cancer, and the Glycolytic Pathway 91
6.30 Hexokinase 92
6.31 Glucose Phosphate Isomerase 93
6.32 Phosphofructokinase 93
6.33 Aldolase 94
6.34 Glyceraldehyde Phosphate Dehydrogenase 95
6.35 Phosphoglycerate Kinase 95
6.36 Enolase 95
6.37 Pyruvate Kinase 95
6.38 Pyruvate Dehydrogenase 96
6.39 Lactate Dehydrogenase and Lactate Carrier MCT4 96
6.40 Glucose Transporters and HIF-1 97
6.41 HIF-1 Upregulation by TCA Intermediates Is Linked to Carcinogenesis 98
6.42 HIF-1 Activity as a Therapeutic Target 98
6.43 Conclusion 98
The Role of Glycolysis in Cellular Immortalization 101
7.44 In Which Stage of Carcinogenesis Is the Warburg Effect Required? 101
1.1 Immortalization and Transformation During Multistep Carcinogenesis 101
1.2 Enhanced Glycolysis Is Required During Transformation to Adapt to Hypoxic Conditions 102
1.3 Oncogene and Glycolysis: ras and c-Myc 103
7.45 Enhanced Glycolysis Is Also Required in Immortalization 104
2.1 Senescence Is a Barrier for Tumorigenesis 104
2.2 Oxidative Stress and Senescence 105
2.3 Senescence-Bypassing Effect of Enhanced Glycolysis 106
2.4 Glycolysis as Radical Scavenger 107
7.46 Opposing Effect of Glycolysis on Life Span Observed in Different Organisms 107
3.1 Discovery of Sir2 as Longevity Gene in Yeast 107
3.2 Calorie Restriction and Sir2 108
7.47 Novel Regulatory Mechanism of Glycolysis 109
4.1 p53 and Glycolysis 109
4.2 PGM and Its Regulation 110
7.48 Conclusion 111
Metabolic Modulation of Carcinogenesis 113
8.49 A Decreased OXPHOS Phenotype Attenuates Apoptosis 114
8.50 Reactive Oxygen Species and Carcinogenesis 114
8.51 The Hexosamine Biosynthetic Pathway 115
8.52 Diversion of Pyruvate from Mitochondria 116
8.53 Organelle and Cell Membrane Perturbations 116
8.54 How Calorie Restriction Inhibits Carcinogenesis 117
8.55 Chronic Infection and Carcinogenesis 119
8.56 Electron Transport Modulation 120
8.57 The Switch to Glycolysis Is Necessary to Induce Apoptosis 121
8.58 Regulation of the Cell Cycle and the Apoptotic Pathway Is Sensitive to Glucose Concentration 122
8.59 Temporal and Spatial Effects in Tumorigenesis 122
8.60 The Warburg Model 123
8.61 Conclusion 125
8.62 Abbreviations 126
Mitochondrial DNA Mutations in Tumors 129
9.63 Introduction 129
9.64 The Mitochondrial Genome 131
9.65 Mitochondrial Genome Instability in Cancer 134
9.66 Homoplasmy and Heteroplasmy in Cancer Cells 135
9.67 Conclusion 136
Cellular Respiration and Tumor Suppressor Genes 141
10.68 Introduction 141
10.69 Otto Warburg and Cellular Respiration 142
10.70 Molecular Homeostasis and Genetic Instability: Genetic Instability and Tumorigenesis 143
10.71 Hypoxia 144
10.72 HRE and HIF-1 145
10.73 Oxygen Sensors 146
10.74 Tumor Microenvironment 146
10.75 Cellular Respiration and Tumor Suppressor Genes 147
8.1 p53 147
8.2 von Hippel--Lindau Syndrome 148
8.3 Interactions Between p53 and VHL 150
10.76 Conclusion 150
Uncoupling Cellular Respiration: A Link to Cancer Cell Metabolism and Immune Privilege 155
11.77 History 155
11.78 An Overview of Cellular Metabolism 155
11.79 Tumor-Specific Metabolic Pathways 156
11.80 Mitochondrial Metabolism 157
11.81 The Immune Response in Cancer 157
11.82 Fundamental Questions 158
11.83 The Immune System and Cancer 158
11.84 Drug Treatment and Fas-Induced Tumor Cell Death 159
11.85 Therapeutic Possibilities 168
How Cancer Cells Escape Death 171
12.86 Introduction 171
12.87 The Bare Pathway to Death 174
2.1 The Family of Bcl-2 Proteins: Initiators of the Intrinsic Pathway 174
2.2 Mitochondrial Outer Membrane Permeability 175
2.3 Caspases Are the Executors of Apoptosis 176
2.4 Changes in Apoptotic Players Associated with Cancer 176
12.88 Deceiving the Surveillance Mechanism by Upregulating Survival Signals 177
3.1 Evading Restrictions Imposed by Cell-Cell Interactions and Tissue Architecture 177
3.2 Autonomous Survival Signals Acquired Through Oncogene Activation and Anti-oncogene Silencing 179
12.89 Survival Effects of Metabolic Changes in Cancer Cells 180
4.1 p53 180
4.2 Glycolysis 181
4.3 Hypoxia 182
4.4 Tumor Acidosis 182
4.5 Mitochondria 183
12.90 Concluding Remarks: Implications for Therapy 184
Index 189