Oncogenes Meet Metabolism (eBook)

Preface 5
Contents 9
List of Editors and Contributors 11
Mitochondria and Cancer 16
1 Introduction 17
2 Mitochondrial Control of Apoptosis 18
3 Therapeutic Interventions for the Restoration of Mitochondrial Apoptosis in Cancer Cells 22
4 Reduced Oxidative Phosphorylation and Carcinogenesis 24
5 Hypothetical Links Between Apoptosis Resistance and Anaerobic Glycolysis at the MitochondrialMembrane 29
References 31
Role of the Metabolic Stress Responses of Apoptosis and Autophagy in Tumor Suppression 38
1 Origins of Metabolic Stress in Tumors 39
2 Activation of Tumor Suppression by Apoptosis in Response to Cellular Stress 40
3 Modulation of the Apoptotic Response by Cancer Therapy 40
4 Inactivation of Apoptosis in Tumor Progression 41
5 Autophagy Mediates Tumor Cell Survival to Metabolic Stress 42
6 Autophagy Is a Tumor Suppression Mechanism 44
7 Autophagy Suppresses Cell Death and Inflammation to Limit Tumor Progression 45
8 Autophagy Prevents Genome Damage to Suppress Tumorigenesis 46
9 Modulation of Tumor Cell Metabolism in Cancer Therapy 47
References 47
The Interplay Between MYC and HIF in the Warburg Effect 50
1 MYC Is a Major Human Oncogene That Encodes a Transcription Factor 51
2 Myc Target Genes in Tumorigenesis 53
3 Myc-E2F Regulatory Axis and DNA Metabolism and Replication 55
4 Effects of Antioxidants on Myc-Mediated Tumorigenesis, Reactive Oxygen Species and the Hypoxia- Inducible Factor 56
5 Collaboration of MYC and HIF in the Warburg Effect 58
References 61
Using Metabolomics to Monitor Anticancer Drugs 70
1 Introduction 71
2 Pharmacodynamic Markers 73
3 Conventional Cytotoxic Drugs 74
4 Cyclin-Kinase Inhibitor 76
5 HSP90 Inhibitor 76
6 Choline Kinase Inhibitor 77
7 HDAC Inhibitors 78
8 Vascular Disruption Agents 79
9 HIF-1a Inhibitor 81
10 PI3K Inhibitor 81
11 MAPK Inhibitor 82
12 Fatty Acid Synthase Inhibitor 82
13 Antimicrotubule Drug 83
14 Discussion 83
References 90
Biomarker Discovery for Drug Development and Translational Medicine Using Metabonomics 94
1 The Potential of the Metabolome to Fill the Biomarker Gap 95
2 Metabonomics in Toxicology 98
3 Metabonomics in Oncology 105
References 109
Pyruvate Kinase Type M2: A Key Regulator Within the Tumour Metabolome and a Tool for Metabolic Profiling of Tumours 114
1 Introduction 115
2 The Pyruvate Kinase Isoenzymes 116
3 Bifunctional Role of the Pyruvate Kinase Isoenzyme Type M2 Within the Tumour Metabolome 118
4 Interaction of M2-PK with Different Oncoproteins 124
5 Role of M2-PK in the Nucleus 130
6 Tumour M2-PK: A Biomarker for Metabolic Profiling of Tumours 130
7 Conclusions 133
References 133
Molecular Imaging of Tumor Metabolism and Apoptosis 140
1 Glucose Metabolism 141
2 AminoAcids 147
3 Apoptosis 155
4 Hypoxia 156
References 159
Minimally Invasive Biomarkers for Therapy Monitoring 168
1 Introduction 169
2 Methods 170
3 Results 175
4 Conclusions 199
References 201
Use of Metabolic Pathway Flux Information in Anticancer Drug Design 204
1 Introduction 205
2 Metabolic Profiles of Tumor Cells 205
3 Tumor Growth-Promoting Signals Influence Phenotype Expression via Nonoxidative Metabolism 208
4 Tumor Growth-Inhibiting Signals Limit Nonoxidative Metabolism 210
5 Metabolic Constraints of Cell Growth 210
6 Concluding Remarks 214
References 215
Cancer Diagnostics Using 1H-NMR-Based Metabonomics 220
1 Background 221
2 Current Status of Early Detection of EOC in the General Population 222
3 NMR-Based Metabonomics for the Analysis of Biofluids 223
4 H-NMR Analysis of Plasma and Cancer Detection 224
5 H-NMR-Based Metabonomics for Ovarian Cancer Detection 225
6 Conclusions and Future Directions 237
References 238
Human Metabolic Phenotyping and Metabolome Wide Association Studies 242
1 Introduction 243
2 Defining the “Normal” Phenotype 244
3 Detecting Pathophenotypes: Diagnostics 247
4 Defining Biomarkers 253
5 TheWayForward 254
References 257
Defining Personal Nutrition and Metabolic Health Through Metabonomics 266
1 Metabonomics Technology Set-up 267
2 Nutrimetabonomics 267
3 The Complex Host–Microbiome Interactions: A Challenge for Nutrition 271
4 Characterizing the Metabolic Status of Individuals: A Step Toward Personalized Nutrition 275
References 276