Mitochondria and Cancer (eBook)

Preface 4
Contents 6
: Mitochondria and Cancer 12
Introduction 12
Mitochondrial Structure 13
Mitochondrial Function 14
Mitochondrial Genome 15
Mitochondria and Cancer 17
Metabolic Differences 17
Changes in Mitochondrial Genome 17
Changes in Nuclear Genome 19
The Role of Mitochondrial ROS in Carcinogenesis 20
Mitochondrial Stress Signaling 21
Mitochondria as Biomarkers for Cancer 23
Mitochondria as Targets for Chemotherapy 24
Acknowledgments 25
References 25
: Warburg and his Legacy 33
Introduction 33
Genetic Control of Glycolysis Involves Tumor Suppressors and Oncogenes 36
Cancer Genes Impose Reduced Mitochondrial Activity 39
The Warburg Effect as Potential Therapeutic Target 41
Summary 42
References 43
: The Lipogenic Switch in Cancer 49
Introduction 49
Lipids in Normal Cell Physiology 49
The Lipogenic Switch in Cancer Cells 52
Mechanism of the Lipogenic Switch in Cancer 53
Lipogenic Enzymes as Potential Targets for Antineoplastic Intervention 56
Impact of Increased Lipogenesis on Tumor Cell Biology 60
Conclusion 61
HeadingsSec7_3 61
References 62
: Citrate Metabolism in Prostate and Other Cancers 70
The Metabolic Roles of Citrate in Normal Mammalian Cells 70
Axioms of Relationships of Cellular Activity, Cellular Metabolism, and Malignancy 72
Citrate Metabolism of Normal Prostate Epithelial Cells: Net Citrate Production 73
Altered Citrate Relationships in Prostate Cancer: The Metabolic Transformation 76
The Metabolic Role of Citrate in Malignancy: Oxidation and/or Cytosolic Acetyl CoA Production 76
The Role of Accelerated Glycolysis in Tumor Cell Metabolism 79
Zinc and Mitochondrial Metabolism Relationships 80
The Clinical Relevancy and Translational Application of Citrate Metabolism in Prostate Cancer 82
HeadingsChap4_41 85
References 85
: Integration of Genetic, Proteomic, and Metabolic Approaches in Tumor Cell Metabolism 88
Introduction - In the Beginning 89
Relationships of Cellular Activity, Cellular Metabolism, and Malignancy - Some Important Axioms 90
Two Important Relationships that Establish the Metabolic Focus of Malignant Cells 91
A Parasitic Existence Defines the Malignant Cell Metabolism 91
The In Situ Environment of the Malignant Cell Dictates its Metabolism 92
Important Cellular Biochemical/Metabolic Relationships 93
Mitochondrial Enzyme/Metabolism Analyses 94
The Concept of Metabolic Genes 95
The Application of Molecular Genetics and Proteomics to Tumor Cell Intermediary Metabolism 96
Acknowledgments 100
References 101
: Mitochondrial Respiration and Differentiation 102
Introduction 102
Mitochondrial Respiration and Cell Differentiation 105
Conclusion 109
References 110
: Integration of Energy Metabolism and Control of Apoptosis in Tumor Cells 112
Introduction 112
The Akt Signaling System, a Survival Pathway that Functions to Facilitate Aerobic Glycolysis 114
Akt Regulation of Hexokinase II in the Control of Energy Metabolism 116
Akt Enhances Cell Survival Mechanisms through its Effects on Mitochondrial Binding of Hexokinase II 118
Akt, Control of Metabolism through mTOR and FOXO 119
AMPK-Survival Under Conditions of Nutrient Scarcity 120
The Role of P53 in Cancer Cell Metabolism 122
Dysregulation of HIF-1 in Cancer Cells and its Impact on Cell Metabolism 125
Pyruvate Kinase as a Regulator of Glycolytic Flux and Apoptosis in Tumor Cells 128
Lactate Dehydrogenase, the Terminal Enzyme of Anaerobic Glycolysis, is Critical for Cancer Cell Metabolism, Proliferation, and 130
Conclusion and Future Directions 131
References 134
: Energy Generating Pathways and the Tumor Suppressor p53 139
Introduction 139
Regulation of Proteins Involved in Glycolysis by p53 141
Proteins Directly Involved in Glycolysis 141
Proteins Indirectly Involved in Glycolysis 145
Proteins Involved in Glucose Import 147
Proteins of the Glycolytic Pathway as Potential Therapeutic Targets 148
Regulation of Proteins Involved in Aerobic Respiration by p53 150
Proteins Directly Involved in Aerobic Respiration 150
Proteins Indirectly Involved in Aerobic Respiration 151
Regulation of p53 by the Products of Glycolysis and Aerobic Respiration 152
Conclusions and Future Directions 153
References 153
: Mitochondrial Tumor Suppressors 159
Introduction 159
Mitochondria 160
Role of Mitochondria in Cancer 160
Krebs Cycle Enzymes and Inherited Tumor Susceptibility 161
Mechanisms of Pathogenesis in PGL 162
Mechanism of Pathogenesis in HLRCC 164
Summary and Conclusions 166
Acknowledgments 167
References 167
: Mitochondria in Hematology 171
Mitochondrial Haplotypes 172
Aging of the Hematological System 173
Aging of Hematological Stem Cells 173
The Drift to Homoplasmy in Aging Cells 175
Leukemogenesis 178
Mitochondrial Enzymes as Tumor Suppressors 178
Hematologic Findings in Mitochondrial Disorders 179
Mitochondrial Hematologic Disorders 180
Pearson´s Syndrome 180
Acquired Idiopathic Sideroblastic Anemia 180
Myelodysplastic Syndromes 182
Mitochondrial Myopathy, Lactic Acidosis, and Sideroblastic Anemia 186
Mitochondria in Hematologic Malignancies 187
Leukemia 187
Lymphoma 188
Potential Pathways of Mitochondrial Leukemogenesis 190
Early Detection of Hematologic Malignancies 192
References 193
: Mitochondria as Targets for Cancer Therapy 217
Introduction: Molecularly Targeted Precision Heralds New-Age Cancer Therapy 217
Targeting Differences in Energy Metabolism between Cancer and Normal Cell Mitochondria to Selectively Destroy Cancer Cells 218
Hypoxia during Cancer Progression Leads to HIF-Induced Changes in Energy Flow to Mitochondria 219
Pseudohypoxia 222
Proton Flux Regulation and Potential Difference across the Mitochondrial Inner Membrane of Cancer Cells 223
Proton Flux across the Plasma Membrane Enables Cancer Cells to Be Selective Targets for Anticancer Drugs 224
ROS, HIF Activation and Changes in Cytochrome C Oxidase Activity 225
Importance of ROS in Tumour Cell Development and Progression and the Residual Respiratory Function of Cancer Cells 227
The Relationship between Thiol Redox Exchange, ROS and Induction of Apoptosis 229
The Adenine Nucleotide Transporter (ANT): Critical Thiol Groups as Targets of Arsenic-Containing Compounds in the Mitochondria 232
The Importance of ROS Production by Mitocans in Triggering Apoptosis: a General Model 234
Types of Mitocans and their Targets 236
Class I: Hexokinase Inhibitors 237
Class II: BH3 Mimetics 238
Class III and IV: Thiol Redox Inhibitors/VDAC- and ANT-Targeting Drugs 239
Class V: Electron Transport Chain-Targeting Drugs 240
Class VI: Lipophilic Cations Targeting the Mitochondrial Inner Membrane 242
Class VII: Drugs Targeting Other Sites 243
Conclusions and Further Perspectives 244
Acknowledgments 244
References 244
: Mitochondria and Oncocytomas 200
Oncocytic Tumors and Oncocytomas 200
Mitochondrial DNA (MtDNA) and Human (degenerative and neoplastic) Disorders 202
Mitochondria and Oncocytic Tumors of the Thyroid (Hürthle cell tumors) 202
Mitochondria and Renal Oncocytomas 207
Mitochondria and Oncocytic Tumors of the Salivary Glands (Warthin's tumor) 209
Mitochondria and Oncocytic Tumors of the Parathyroid 210
Familial Oncocytomas 211
Acknowledgements 213
References 213
: Reversing the Warburg Effect: Metabolic Modulation as a Novel Cancer Therapy 256
Introduction 256
Metabolism in the Evolutionary and Genetic Models of Cancer Development 257
A Mitochondria-K+ Channel Axis and the Regulation of Apoptosis (Fig.1) 259
Mitochondria in Cancer 261
DCA in Cancer: Preclinical Work 262
DCA in the Treatment of Congenital Mitochondrial Diseases 263
DCA: Clinical Translation in Oncology 266
References 267
: Mitochondrial Nanotechnology for Cancer Therapy 270
Introduction 270
Nanotechnology and Cancer Therapy 271
Cytosolic Barriers to Mitochondrial Drug Delivery 273
Physicochemical Properties Determining a Drug's Mitochondria-Specific Bioavailability 274
Mitochondria-Targeted Nanodrug Delivery Systems 275
DQAsomes as the Prototype for Mitochondria-Specific Nanotechnology 276
Mitochondria-Specific Nanolipid Vesicles (Liposomes) 279
Gold Nanoparticles Suited for Mitochondrial Targeting 280
Summary 281
References 282