Cell Signaling & Molecular Targets in Cancer (eBook)

Cell Signaling & MolecularTargets in Cancer
Acknowledgement 5
Contents 7
Contributors 9
Chapter 1: GRB2 Signaling as a Molecular Target for Cancer 13
Introduction 13
Adaptor Proteins in Cell Signaling 13
The Grb Family 14
The Adaptor Protein GRB2 15
Grb2 in Cell Signaling 15
Grb2 and Cancer 17
Involvement of Grb2 in Invasion and Metastasis 18
Grb2 Involvement in the Early Phases of the Metastatic Cascade 19
Role of Grb2 in Angiogenesis and Dissemination 24
Development of Grb2 Inhibitors as Anticancer Drugs 26
Conclusions and Prospectives 29
References 30
Chapter 2: Human Arylamine N -acetyltransferase 1: From Drug Metabolism to Drug Target 35
Introduction 35
Human NAT1 Gene Structure and Polymorphism 37
Human NAT1 Protein Structure 40
Animal Models to Understand NAT1 Functions 41
Possible Relevance of NAT1 in Cancer 42
NAT1 as a Drug Target in Cancer 43
References 45
Chapter 3: Targeting Argininosuccinate Synthetase in Cancer Therapy 48
Introduction 48
Background 48
Why Arginine Deprivation Is Important 49
Preclinical Antitumor Activity of ADI-PEG20 51
ASS Expression and Arginine Deprivation in Melanoma 51
Arginine Deprivation in Hepatocellular Carcinoma 52
Arginine Deprivation in Other Tumor Cell Types 53
How Arginine Deprivation Affects Growth and Apoptotic Signaling 53
Arginine Deprivation Affects mTOR Signaling 53
Arginine Deprivation on RAF/MEK/ERK1/2 Signaling 54
Arginine Deprivation Leads to Autophagy in ASS( ) Cells 54
How Arginine Deprivation Induces Cell Death in ASS( ) Melanoma Cells 55
ASS Expression and Cisplatin Resistance 56
Other Effects of Arginine Deprivation 57
Clinical Trials with ADI-PEG20 58
Concluding Remarks and Future Direction 59
References 60
Chapter 4: Parathyroid Hormone–Related Peptide Signaling in Cancer* 63
Introduction 63
PTHrP Gene Structure and Regulation 64
Cancer Cell Growth 68
Regulation of ERK1/2 by G s 73
Regulation of ERK1/2 by G a q 75
Apoptosis 77
Invasiveness and Integrins 79
PTHRP and Bone Metastases 83
References 88
Chapter 5: Signalling Molecules as Selective Targets for Therapeutic Strategies in Multiple Myeloma 96
Epidemiology and Aetiology 96
Pathobiology of MM 96
Targeting Growth- and Survival-Promoting Signalling Cascades in MM PCs 98
The IL-6 Signalling System 98
IGF-I Signalling 101
The NF- k B Pathway 101
The PI3K/AKT Pathway 102
Bcl-2 Protein Family 102
Farnesyltransferase Inhibitors (FTIs) 103
TRAIL 104
Targeting Protein Maturation, Degradation and Acetylation 104
Hsp90 Inhibitors 104
Proteasome Inhibitors 105
Bortezomib 105
NPI-0052 106
Carfilzomib (PR-171) 106
HDAC Inhibitors 106
Targeting the Myeloma Malignant Bone Marrow Microenvironment 107
Immunomodulatory Therapies 107
Anti-angiogenic Therapy 108
VEGF Inhibitors 108
Fibroblast Growth Factor Receptor 3 (FGFR3) Inhibitors 109
Other Signalling Pathways 109
P38 MAP Kinase Inhibitors 109
TGF b Inhibitors 109
Summary 110
References 110
Chapter 6: Role of Bile Acids in Carcinogenesis of Gastrointestinal Tract 118
Introduction 118
Bile Acids and Carcinogenesis 119
Bile Acids and COX-2 Expression in Gastrointestinal Carcinogenesis 120
Bile Acids and Human Gastrointestinal Cancer 121
Esophagus 121
Esophageal Squamous Cell Carcinoma 121
Barrett’s Epithelium and Esophageal Adenocarcinoma 121
CDX-2 and Barrett’s Epithelium 122
COX-2 Expression and Bile Acids in Esophageal Adenocarcinoma 122
Stomach 123
Gastric Carcinogenesis and Duodeno-gastric Reflux 123
Gastric Carcinogenesis and COX-2 124
Colorectal Cancer 125
Colon Cancer and Bile Acids 125
Colorectal Cancer and COX-2 126
Bile Acid Receptors and Gastrointestinal Carcinogenesis 127
GPCR and EGFR Crosstalk and Carcinogenesis 127
Bile Acid Receptors and EGFR Transactivation 128
Bile Acids as Ligands for GPCR 129
M 3 Muscarinic Receptor and EGFR Activation 129
TGR5 and EGFR Transactivation 129
FXR and Colon Carcinogenesis 130
Conclusions 132
References 132
Chapter 7: AIB1: A Transcriptional Coactivator Which Integrates Signaling Cross Talk in Cancer Cells 138
Introduction: Cancer Etiology and Signal Transduction 138
The Steroid Receptor Coactivator or p160 Family 140
Role of AIB1 in Physiology 145
Role of AIB1 During Development 145
Role of AIB1 in Reproductive Tissues 146
Role of AIB1 in the Central Nervous System 147
Role of AIB1 in Energy Homeostasis 147
Role of AIB1 in Other Tissues 148
Overexpression of AIB1 Affects Both Cancer Initiation and Progression 149
Evidences from Biopsies and Animal Models 149
Mechanisms of AIB1 Oncogenic Activity 152
Hormone-Dependent Mechanisms: The Steroid Receptor Signaling 152
Hormone-Independent Mechanisms 154
The IGF/PI3K/AKT Signaling Pathway 154
The ErbB/HER Signaling Pathway 156
The NF-.B Signaling Pathway 156
The Rb/E2F1 Signaling Pathway 157
Invasiveness Mechanisms 157
Cell Cycle Regulation by AIB1 159
IGF-I Is a Mediator of AIB1 Signaling 161
Overexpression of AIB1 and HER2/NEU Correlates with Tamoxifen Resistance 163
Predictive and Prognostic Factors: Targeting AIB1 in Cancer Therapy 165
References 168
Chapter 8: Rational Design of DNA Anticancer Agent That Targets Signal Transducer and Activator of Transcription 3 (Stat3) for Cancer Therapy 176
Introduction 176
Developed Inhibitors of Stat3 Signaling 178
Organic Compounds 178
Peptide Inhibitors 178
DNA Inhibitors 179
Protein Inhibitors 179
G-Quartet Oligodeoxynucleotides (GQ-ODNs) as a Potential Anticancer Drug 179
Rational Design of G-Rich ODNs That Target Stat3 Signaling 181
Structure-Based Drug Design 181
GQ-ODN T40214 Selectively Inhibiting Stat3 Activation 181
An Effective Drug Delivery System for GQ-ODNs 183
The Drug Activity of GQ-ODN Was Greatly Increased by the Effective Delivery 186
Drug Activity in Cancer Cells 186
Drug Delivery and Activity In Vivo 186
T40214 Suppresses the Growth of Prostate Tumor Xenografts in Nude Mice 188
Prostate Cancer Therapy 188
Other Solid Tumor Therapies 188
The Mechanism of GQ-ODN T40214 as a Potent Anticancer Agent 191
The Mechanism of T40214 Suppression of Tumor Growth 191
T40214 as an Anticancer Agent Targeting Stat3 Signaling for Cancer Therapy 191
Toxicity of GQ-ODN T40214/PEI Complex 194
Toxicity of GQ-ODNs: G-Quartet ODNs Are Low-Toxicity Agents 194
Toxicity of PEI 194
T40214/PEI Complex Shows No Toxicity 194
Summary 196
Stat3: An Important Target in Cancer Therapy 196
Potential Impact of T40214 on Cancer Therapy 196
References 197
Chapter 9: Estrogen Receptor Signaling in Lung Cancer 200
Introduction 200
Estrogen Receptors Mediating Estrogen Action 201
Lung: An Estrogen-Responsive Tissue 203
Effects of Endogenous and Exogenous Estrogens (Hormone Replacement Therapy) on Lung Cancer Risk and Lung Cancer Outcomes 204
Preclinical Studies Indicating that Estrogen Supports the Development or Growth of NSCLC 205
Evaluation of the Functionality of the Classical Genomic Estrogen-Signaling Pathway in NSCLC Cells 206
Membrane-Initiated Steroid Signaling (MISS) in Lung Epithelial Cells and NSCLC 206
Estrogen Receptors and Mitochondria 207
Estrogen Receptors Expressed in NSCLC Cells and Human Primary Lung Tumors 209
Using Subtype Selective Ligands to Assess the Relative Contributions of ER b and ER a in NSCLC Cell Lines 210
E2 Cooperates with Growth Factor Receptor Signaling to Increase the Growth of NSCLC Cells 211
Aromatase 213
Summary and Future Directions 215
References 215
Chapter 10: Microparticle Dissemination of Biological Activities: Implications for Cancer Biology 220
Introduction 220
Cell-Derived Microparticles 221
Mechanism of MP Generation, Release, and Action 221
Stimuli Triggering MP Generation 222
Measurement of MP 224
Role of Cell-Derived MPS in Tumor Growth, Angiogenesis, and Metastasis 225
Tumor Progression and Metastasis 225
Tumor Cell-Derived MPs (TMPs) and Tumor Growth, Angiogenesis, and Metastasis 225
TMPs and Tumor Invasion and Metastasis 226
TMPs and Tumor-Induced Angiogenesis 227
TMPs and Immune Escape 231
TMPs and Trafficking to Metastatic Foci 232
Platelet-Derived MP (PMP) and Tumor Growth, Angiogenesis, and Metastasis 234
Tissue Factor-Positive Microparticles and Cancer-Associated Thrombosis 236
Cancer-Associated Thrombosis 236
Tissue Factor in Cancer-Associated Thrombosis 236
Studies Implicating Tissue Factor-Positive MPs in Cancer-Associated Thrombosis 237
Tissue Factor-Positive MPs – Cellular Origin and Procoagulant Activity 239
Protein Disulfide Isomerase – Potential Modulator of TF Activity 240
Proposed Model for Promotion of Thrombus Development by TF-Expressing MP and Platelet-Derived PDI 243
Conclusion and Future Perspectives 244
References 246
Chapter 11: Protein Kinase D Signaling in Cancer 253
Introduction 253
Activation of PKD 256
Upstream Activators for PKD 256
Signaling Mechanisms Regulating PKD Activity 258
Role of PKD in Tumor Cell Proliferation 260
Role of PKD in Tumor Cell Survival Signaling 262
Functions of PKD in Chemoresistance 263
Role of PKD in Tumor Cell Migration and Invasion 264
Regulation of PKD Expression in Cancer 267
PKD as a Regulator of Angiogenesis 268
Perspective 269
References 271
Chapter 12: Cell Signaling and Cancer: Integrated, Fundamental Approach Involving Electron Transfer, Reactive Oxygen Species, and Antioxidants 280
Introduction 280
Tenets of OS Theory 281
Chronology 282
Stages in Carcinogenesis 282
Cell Signaling 283
Integrated Approach 284
Endogenous Agents 284
Exogenous Agents 288
Metals and Particulates 288
Ultraviolet (UV) Radiation 289
Hydrogen Peroxide 289
Alcohol 290
Ginkgo Biloba 290
Curcumin 290
Endosulfan 290
Benzene 290
Polycyclic Aromatic Hydrocarbons (PAHs) 291
Estrogen Quinone 291
Antioxidants 291
Chemotherapeutic Agents and Preventions 292
Aminoflavone 292
Curcumin 293
Radiation 293
Nitric Oxide 293
Resveratrol 293
Polyphenols 293
Formaldehyde 294
Isoobtusilactone (IOA) 294
Genipin 294
Decursin 294
Quinoline Quinone 294
Acacetin 295
Berberine 295
PAC-1 and UCS1025A 295
Selenium 295
Dialkyl Disulfide (DADS) 295
Onion 296
SOD 296
Phytochemicals 296
References 296
Chapter 13: Targeting Signal Transducer and Activator of Transcription (STAT) for Anticancer Therapy* 305
Introduction 305
Structure and Function of STATs 306
STAT Activation–Inactivation Cycle 306
STAT Function 307
STAT Phosphorylation and Activation 308
STAT Serine Phosphorylation and Other STAT Modifications 309
Activation of Transcription 309
Protein Inhibitor of Activated STAT 309
STAT and Tumor Biology 310
Overview 310
Constitutive Activation of STATs in Cancer 310
STATs and Tumor Cell Proliferation and Resistance to Apoptosis 311
STATs and Tumor Angiogenesis 312
Role of STATs in Evading Immune Surveillance Mechanisms 313
Targeting STATS 314
Peptidic Inhibitors and Peptidomimetic Inhibitors 314
Small-Molecule Non-peptidic Inhibitors 314
Inhibitors of STAT DNA Binding Domains 315
Inhibitors of the N-Terminal Domain 316
Oligonucleotides Targeting STAT3 317
Tyrosine Kinase Inhibitors 318
Natural Compounds 318
Other Compounds with STAT3 Inhibitory Activity 321
Activators of STAT Inhibitors 322
Conclusion 322
References 322
Index 328