Singh / Costello Mitochondria and Cancer

1. Auflage 2009
ISBN: 978-0-387-84835-8
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 289 Seiten

An exhaustive analysis of the role of mitochondria in cancer, this book surveys the Warburg Hypothesis, mitochondrial structure and function, and then outlines the metabolic and molecular alterations in mitochondria that are associated with human cancer.

Autoren/Hrsg.

Singh, Keshav

Costello, Leslie

Inhaltsverzeichnis

1;Preface;4
2;Contents;6
3;: Mitochondria and Cancer;12
3.1;Introduction;12
3.2;Mitochondrial Structure;13
3.3;Mitochondrial Function;14
3.4;Mitochondrial Genome;15
3.5;Mitochondria and Cancer;17
3.5.1;Metabolic Differences;17
3.5.2;Changes in Mitochondrial Genome;17
3.5.3;Changes in Nuclear Genome;19
3.5.4;The Role of Mitochondrial ROS in Carcinogenesis;20
3.5.5;Mitochondrial Stress Signaling;21
3.5.6;Mitochondria as Biomarkers for Cancer;23
3.5.7;Mitochondria as Targets for Chemotherapy;24
3.6;Acknowledgments;25
3.7;References;25
4;: Warburg and his Legacy;33
4.1;Introduction;33
4.2;Genetic Control of Glycolysis Involves Tumor Suppressors and Oncogenes;36
4.3;Cancer Genes Impose Reduced Mitochondrial Activity;39
4.4;The Warburg Effect as Potential Therapeutic Target;41
4.5;Summary;42
4.6;References;43
5;: The Lipogenic Switch in Cancer;49
5.1;Introduction;49
5.2;Lipids in Normal Cell Physiology;49
5.3;The Lipogenic Switch in Cancer Cells;52
5.4;Mechanism of the Lipogenic Switch in Cancer;53
5.5;Lipogenic Enzymes as Potential Targets for Antineoplastic Intervention;56
5.6;Impact of Increased Lipogenesis on Tumor Cell Biology;60
5.7;Conclusion;61
5.8;HeadingsSec7_3;61
5.9;References;62
6;: Citrate Metabolism in Prostate and Other Cancers;70
6.1;The Metabolic Roles of Citrate in Normal Mammalian Cells;70
6.2;Axioms of Relationships of Cellular Activity, Cellular Metabolism, and Malignancy;72
6.3;Citrate Metabolism of Normal Prostate Epithelial Cells: Net Citrate Production;73
6.4;Altered Citrate Relationships in Prostate Cancer: The Metabolic Transformation;76
6.5;The Metabolic Role of Citrate in Malignancy: Oxidation and/or Cytosolic Acetyl CoA Production;76
6.6;The Role of Accelerated Glycolysis in Tumor Cell Metabolism;79
6.7;Zinc and Mitochondrial Metabolism Relationships;80
6.8;The Clinical Relevancy and Translational Application of Citrate Metabolism in Prostate Cancer;82
6.9;HeadingsChap4_41;85
6.10;References;85
7;: Integration of Genetic, Proteomic, and Metabolic Approaches in Tumor Cell Metabolism;88
7.1;Introduction - In the Beginning;89
7.2;Relationships of Cellular Activity, Cellular Metabolism, and Malignancy - Some Important Axioms;90
7.3;Two Important Relationships that Establish the Metabolic Focus of Malignant Cells;91
7.3.1;A Parasitic Existence Defines the Malignant Cell Metabolism;91
7.3.2;The In Situ Environment of the Malignant Cell Dictates its Metabolism;92
7.4;Important Cellular Biochemical/Metabolic Relationships;93
7.5;Mitochondrial Enzyme/Metabolism Analyses;94
7.6;The Concept of Metabolic Genes;95
7.7;The Application of Molecular Genetics and Proteomics to Tumor Cell Intermediary Metabolism;96
7.8;Acknowledgments;100
7.9;References;101
8;: Mitochondrial Respiration and Differentiation;102
8.1;Introduction;102
8.2;Mitochondrial Respiration and Cell Differentiation;105
8.3;Conclusion;109
8.4;References;110
9;: Integration of Energy Metabolism and Control of Apoptosis in Tumor Cells;112
9.1;Introduction;112
9.1.1;The Akt Signaling System, a Survival Pathway that Functions to Facilitate Aerobic Glycolysis;114
9.1.2;Akt Regulation of Hexokinase II in the Control of Energy Metabolism;116
9.1.3;Akt Enhances Cell Survival Mechanisms through its Effects on Mitochondrial Binding of Hexokinase II;118
9.1.4;Akt, Control of Metabolism through mTOR and FOXO;119
9.2;AMPK-Survival Under Conditions of Nutrient Scarcity;120
9.3;The Role of P53 in Cancer Cell Metabolism;122
9.4;Dysregulation of HIF-1 in Cancer Cells and its Impact on Cell Metabolism;125
9.5;Pyruvate Kinase as a Regulator of Glycolytic Flux and Apoptosis in Tumor Cells;128
9.6;Lactate Dehydrogenase, the Terminal Enzyme of Anaerobic Glycolysis, is Critical for Cancer Cell Metabolism, Proliferation, and;130
9.7;Conclusion and Future Directions;131
9.8;References;134
10;: Energy Generating Pathways and the Tumor Suppressor p53;139
10.1;Introduction;139
10.2;Regulation of Proteins Involved in Glycolysis by p53;141
10.2.1;Proteins Directly Involved in Glycolysis;141
10.2.2;Proteins Indirectly Involved in Glycolysis;145
10.2.3;Proteins Involved in Glucose Import;147
10.2.4;Proteins of the Glycolytic Pathway as Potential Therapeutic Targets;148
10.3;Regulation of Proteins Involved in Aerobic Respiration by p53;150
10.3.1;Proteins Directly Involved in Aerobic Respiration;150
10.3.2;Proteins Indirectly Involved in Aerobic Respiration;151
10.4;Regulation of p53 by the Products of Glycolysis and Aerobic Respiration;152
10.5;Conclusions and Future Directions;153
10.6;References;153
11;: Mitochondrial Tumor Suppressors;159
11.1;Introduction;159
11.1.1;Mitochondria;160
11.1.2;Role of Mitochondria in Cancer;160
11.2;Krebs Cycle Enzymes and Inherited Tumor Susceptibility;161
11.3;Mechanisms of Pathogenesis in PGL;162
11.4;Mechanism of Pathogenesis in HLRCC;164
11.5;Summary and Conclusions;166
11.6;Acknowledgments;167
11.7;References;167
12;: Mitochondria in Hematology;171
12.1;Mitochondrial Haplotypes;172
12.2;Aging of the Hematological System;173
12.2.1;Aging of Hematological Stem Cells;173
12.2.2;The Drift to Homoplasmy in Aging Cells;175
12.3;Leukemogenesis;178
12.3.1;Mitochondrial Enzymes as Tumor Suppressors;178
12.4;Hematologic Findings in Mitochondrial Disorders;179
12.5;Mitochondrial Hematologic Disorders;180
12.5.1;Pearson´s Syndrome;180
12.5.2;Acquired Idiopathic Sideroblastic Anemia;180
12.5.3;Myelodysplastic Syndromes;182
12.5.4;Mitochondrial Myopathy, Lactic Acidosis, and Sideroblastic Anemia;186
12.6;Mitochondria in Hematologic Malignancies;187
12.6.1;Leukemia;187
12.6.2;Lymphoma;188
12.6.3;Potential Pathways of Mitochondrial Leukemogenesis;190
12.6.4;Early Detection of Hematologic Malignancies;192
12.7;References;193
13;: Mitochondria as Targets for Cancer Therapy;217
13.1;Introduction: Molecularly Targeted Precision Heralds New-Age Cancer Therapy;217
13.2;Targeting Differences in Energy Metabolism between Cancer and Normal Cell Mitochondria to Selectively Destroy Cancer Cells;218
13.3;Hypoxia during Cancer Progression Leads to HIF-Induced Changes in Energy Flow to Mitochondria;219
13.4;Pseudohypoxia;222
13.5;Proton Flux Regulation and Potential Difference across the Mitochondrial Inner Membrane of Cancer Cells;223
13.6;Proton Flux across the Plasma Membrane Enables Cancer Cells to Be Selective Targets for Anticancer Drugs;224
13.7;ROS, HIF Activation and Changes in Cytochrome C Oxidase Activity;225
13.8;Importance of ROS in Tumour Cell Development and Progression and the Residual Respiratory Function of Cancer Cells;227
13.9;The Relationship between Thiol Redox Exchange, ROS and Induction of Apoptosis;229
13.10;The Adenine Nucleotide Transporter (ANT): Critical Thiol Groups as Targets of Arsenic-Containing Compounds in the Mitochondria;232
13.11;The Importance of ROS Production by Mitocans in Triggering Apoptosis: a General Model;234
13.12;Types of Mitocans and their Targets;236
13.12.1;Class I: Hexokinase Inhibitors;237
13.12.2;Class II: BH3 Mimetics;238
13.12.3;Class III and IV: Thiol Redox Inhibitors/VDAC- and ANT-Targeting Drugs;239
13.12.4;Class V: Electron Transport Chain-Targeting Drugs;240
13.12.5;Class VI: Lipophilic Cations Targeting the Mitochondrial Inner Membrane;242
13.12.6;Class VII: Drugs Targeting Other Sites;243
13.13;Conclusions and Further Perspectives;244
13.14;Acknowledgments;244
13.15;References;244
14;: Mitochondria and Oncocytomas;200
14.1;Oncocytic Tumors and Oncocytomas;200
14.2;Mitochondrial DNA (MtDNA) and Human (degenerative and neoplastic) Disorders;202
14.3;Mitochondria and Oncocytic Tumors of the Thyroid (Hürthle cell tumors);202
14.4;Mitochondria and Renal Oncocytomas;207
14.5;Mitochondria and Oncocytic Tumors of the Salivary Glands (Warthin's tumor);209
14.6;Mitochondria and Oncocytic Tumors of the Parathyroid;210
14.7;Familial Oncocytomas;211
14.8;Acknowledgements;213
14.9;References;213
15;: Reversing the Warburg Effect: Metabolic Modulation as a Novel Cancer Therapy;256
15.1;Introduction;256
15.2;Metabolism in the Evolutionary and Genetic Models of Cancer Development;257
15.3;A Mitochondria-K+ Channel Axis and the Regulation of Apoptosis (Fig.1);259
15.4;Mitochondria in Cancer;261
15.5;DCA in Cancer: Preclinical Work;262
15.6;DCA in the Treatment of Congenital Mitochondrial Diseases;263
15.7;DCA: Clinical Translation in Oncology;266
15.8;References;267
16;: Mitochondrial Nanotechnology for Cancer Therapy;270
16.1;Introduction;270
16.2;Nanotechnology and Cancer Therapy;271
16.3;Cytosolic Barriers to Mitochondrial Drug Delivery;273
16.4;Physicochemical Properties Determining a Drug's Mitochondria-Specific Bioavailability;274
16.5;Mitochondria-Targeted Nanodrug Delivery Systems;275
16.5.1;DQAsomes as the Prototype for Mitochondria-Specific Nanotechnology;276
16.5.2;Mitochondria-Specific Nanolipid Vesicles (Liposomes);279
16.5.3;Gold Nanoparticles Suited for Mitochondrial Targeting;280
16.6;Summary;281
16.7;References;282