Understanding the importance and necessity of the role of autophagy in health and disease is vital for the studies of cancer, aging, neurodegeneration, immunology, and infectious diseases. Comprehensive and up-to-date, this book offers a valuable guide to these cellular processes whilst inciting researchers to explore their potentially important connections. Volume 5 comprehensively describes the role of autophagy in human diseases, delivering coverage of the antitumor and protumor roles of autophagy; the therapeutic inhibition of autophagy in cancer; and the duality of autophagy's effects in various cardiovascular, metabolic, and neurodegenerative disorders. In spite of the increasing importance of autophagy in the various pathophysiological conditions mentioned above, this process remains underestimated and overlooked. As a consequence, its role in the initiation, stability, maintenance, and progression of these and other diseases remains poorly understood. This book is an asset to newcomers as a concise overview of the diverse disease implications of autophagy, while serving as an excellent reference for more experienced scientists and clinicians looking to update their knowledge. Volumes in the Series
Front Cover 1
Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging 4
Copyright Page 5
Dedication 6
Mitophagy and Biogenesis 8
Autophagy and Cancer 12
Contents 14
Foreword by Roberta A. Gottlieb 18
Foreword by Eeva-Liisa Eskelinen 20
Preface 22
Contributors 26
Abbreviations and Glossary 30
Autophagy: Volume 1 – Contributions 40
Autophagy: Volume 2 – Contributions 42
Autophagy: Volume 3 – Contributions 44
Autophagy: Volume 4 – Contributions 46
1 Introduction to Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, Volume 5 48
Introduction 49
Specific Functions of Autophagy (A Summary) 51
Autophagy in Normal Mammalian Cells 51
Endoplasmic Reticulum Stress and Autophagy 52
Major Types of Autophagies 53
Macroautophagy (Autophagy) 54
Microautophagy 54
Chaperone-Mediated Autophagy 54
Autophagosome Formation 55
Autophagic Lysosome Reformation 56
Autophagic Proteins 57
Protein Degradation Systems 58
Beclin 1 58
Non-Autophagic Functions of Autophagy-Related Proteins 59
Microtubule-Associated Protein Light Chain 3 60
Monitoring Autophagy 60
Reactive Oxygen Species (ROS) 61
Mammalian Target of Rapamycin (mTOR) 61
Role of Autophagy in Tumorigenesis and Cancer 62
Role of Autophagy in Immunity 64
Autophagy and Senescence 66
Role of Autophagy in Viral Defense and Replication 66
Role of Autophagy in Intracellular Bacterial Infection 67
Role of Autophagy in Heart Disease 68
Role of Autophagy in Neurodegenerative Diseases 69
Cross-Talk between Autophagy and Apoptosis 71
Autophagy and Ubiquitination 75
Aggresome: Ubiquitin Proteasome and Autophagy Systems 76
Autophagy and Necroptosis 76
Mitochondrial Fusion and Fission 77
Selective Autophagies 78
Allophagy 78
Glycophagy 79
Pexophagy 84
References 88
I. Role of Autophagy in Cancer 96
2 Molecular Cross-Talk between the Autophagy and Apoptotic Networks in Cancer 98
Introduction 99
Dual Effector Molecules of Autophagy and Apoptosis 100
Bcl-2 100
Beclin 101
Atg5 102
Atg12 102
UVRAG 103
Molecular Cross-Talk between Autophagy and the UbiqUitin + Proteasome System 103
Molecular Linkage of the Ups with Aggresomes and Selective Autophagy 107
Conclusion 108
References 109
3 Inhibition of ErbB Receptors and Autophagy in Cancer Therapy 112
Introduction 113
Autophagy 113
ErbB Family of Receptor Tyrosine Kinases 114
EGFR (ErbB1) and Autophagy 116
ErbB2 (HER2/NEU) and Autophagy 121
ErbB3 and ErbB4 and Autophagy 123
Discussion 123
Acknowledgments 125
References 125
4 Ginsenoside F2 Initiates an Autophagic Progression in Breast Cancer Stem Cells 128
Introduction 129
Autophagy 129
Major Molecular Components in Autophagy 129
Cross-Talk between Apoptosis and Autophagy 130
Autophagy Induced by Ginsenoside F2 in Breast Cancer Stem Cells 130
Ginsenoside F2 Induces Autophagy in Breast CSCs 130
F2 Induces Autophagy through the Modulation of p53 131
Mechanism for the Effects of F2 on Breast CSCs 131
Discussion 134
Acknowledgments 136
References 136
5 Role of Autophagy in Cancer Therapy 138
Introduction 139
Autophagy and Cell Signaling 140
Autophagy and Cell Death: Implication in Cancer 142
The Role of Autophagy in Cancer is Context Dependent: Oncogene Transformation Versus Established Tumors 144
Mitophagy, ROS, and Cancer 145
Cancer Stem Cells and Autophagy 146
Cancer Therapy by Modulating Autophagy 147
Discussion 147
References 149
6 Autophagy in Human Brain Cancer: Therapeutic Implications 152
Introduction 153
Background on Autophagy 154
Autophagy and its Flux 155
Autophagy-Dependent Control of Cell Survival and Cell Death 156
Expression of Autophagy Regulators and Associated Factors in Human Glioblastoma Tissue 157
Signaling Pathways, miRNA Regulating Autophagy, and Glioblastoma 159
Therapeutic Perspectives Related to Autophagy in Glioblastoma 161
Should We Switch Autophagy On or Off in Order to Combat Glioblastoma? 161
Autophagy Inhibitors in Cancer Treatment 161
Autophagy Inducers in Cancer Treatment 163
Switch between Apoptosis and Autophagy 165
Conclusion 166
References 166
7 Blockage of Lysosomal Degradation Is Detrimental to Cancer Cell Survival: Role of Autophagy Activation 168
Introduction 169
Lysosomes 170
Normal Function of Lysosomes 170
Lysosomal Hydrolases 170
Cathepsin D 171
Cathepsins B and L 171
Pathways Converging in Lysosomes 172
Lysosomal Regulation of Autophagy 172
Lysosomal Membrane Permeability (LMP) 173
Blockage of Lysosomal Degradation in Cancer 173
Insufficient Lysosomal Function Impairs Autophagy 174
Targeting Cathepsins in the Treatment of Cancer 174
Targeting Lysosomes in Cancer Therapy 176
Discussion 177
Acknowledgments 179
References 179
8 Induction of Protective Autophagy in Cancer Cells by NAE Inhibitor MLN4924 182
Introduction 183
Autophagy 183
Characteristics of Autophagy 183
Autophagy in Tumorigenesis and Anticancer Therapy 184
Neddylation 185
Post-translational Modification via Neddylation 185
Neddylation Substrate cullin-RING E3 Ligase (CRL) as an Anticancer Target 185
MLN4924, a Small Molecule Inhibitor of NAE 186
NAE Enzyme Inhibitor MLN4924 as a First-In-Class Anticancer Agent 186
MLN4924 Triggers Autophagic Responses in Cancer Cells 186
MLN4924-Induced Autophagy is Protective and Serves as a Survival Signal 186
Critical Role of the mTOR–DEPTOR Axis in MLN4924-Induced Autophagy 187
Discussion 187
References 189
9 Effect of Autophagy on Chemotherapy-Induced Apoptosis and Growth Inhibition 192
Introduction 193
Autophagy and Chemotherapy-Induced Apoptosis and Growth Inhibition 194
Autophagy Restrains Chemotherapy-Induced Apoptosis 194
Autophagy Promotes Chemotherapy-Induced Apoptosis 195
Autophagy Aggravates Chemotherapy-Induced Growth Inhibition 196
Autophagy, Tumor Microenvironment, and Chemoresistance 196
Hypoxia-Induced Autophagy Contributes to Chemoresistance of Tumor Cells 196
Hypoxia-Induced Autophagy Contributes to Tolerance of Tumor Cells to Nutrient Deprivation in Tumor Microenvironment 197
Autophagy and DNA Damage-Inducing Chemotherapy 198
Autophagy Can Be Induced by DDRs in DNA Damaged Cells 198
Autophagy Regulates DDRs by Indirect and Direct Approaches 199
Autophagy Essential Proteins Regulate DDR by Autophagy-Independent Means 199
Autophagy and Cancer Stem Cells in Chemoresistance 199
Autophagy Is Essential for Maintenance of the Tumorigenicity of CSCs 199
Autophagy Contributes to Survival of CSCs in Oxygen and/or Nutrient-Deprived Tumor Microenvironment 200
Autophagy Involved in CSC Chemoresistance 200
Conclusion 201
References 201
10 Autophagy Upregulation Reduces Doxorubicin-Induced Cardiotoxicity 204
Introduction 205
Anthracycline-Induced Cardiotoxicity 206
What Is Cardiotoxicity? 206
Classification of Anthracycline-Induced Cardiotoxicity 206
Mechanisms of Cardiotoxicity 207
The Oxidative Stress Hypothesis 209
Autophagy 211
Signaling Pathways Regulating Autophagy 212
Oxidative Stress and Autophagy 213
The Role of Autophagy in Heart Disease and Cancer 214
Autophagy Induction as a Mechanism to Reduce Doxorubicin-Induced Cardiotoxicity 215
Summary 217
Acknowledgments 218
References 218
II. Role of Autophagy in Cardiovascular, Metabolic, and Neurodegenerative Diseases 222
11 Autophagy in Critical Illness 224
Introduction 224
The Formation and Regulation of Autophagy 225
Autophagy in Critical Illness – the Role of Nutrient Restriction, Deprivation, and/or Starvation 227
Autophagy in Brain Injury 228
Basal Neuronal Autophagy 228
Traumatic Brain Injury 228
Intracerebral and Subarachnoid Hemorrhage 229
Autophagy in Infection and Inflammation 230
Therapeutic Target 234
References 235
12 Autophagy in the Onset of Atrial Fibrillation 240
Introduction 241
Mechanisms of Atrial Fibrillation 241
Drugs used for Treating Atrial Fibrillation 242
Autophagy in Atrial Fibrillation 243
Potential Role of Modulators of Autophagy in the Treatment of Atrial Fibrillation 245
Conclusion 246
Acknowledgments 246
References 246
13 Role of Autophagy in Atherogenesis 250
Introduction 251
Autophagy in the Major Cell Types Involved in Atherosclerosis 251
Endothelial Cells 251
Vascular Smooth Muscle Cells (VSMCs) 252
Macrophages 253
Role of Autophagy in Lipid Metabolism 253
Autophagy and ApoB-containing Lipoproteins 253
Autophagy and Sterol Regulatory Element Binding Proteins (SREBPs): A Two-Way Regulatory Pathway 254
Autophagy, Cholesterol Efflux, and Reverse Cholesterol Transport 254
Recent Discoveries About Autophagy and Atherosclerosis in Animal Models 255
Autophagy: A Target for Atherosclerosis Treatment 256
Conclusion 256
Acknowledgments 256
References 256
14 Regulation of Autophagy in Insulin Resistance and Type 2 Diabetes 260
Introduction 261
Main Regulatory Mechanisms 262
Nutrients and Growth Factors 262
Energy Status 262
Endoplasmic Reticulum Stress 262
Forkhead Box O (FoxO) Transcription Factors 264
Regulation of Autophagy in Insulin Resistance or T2DM in Different Organs 264
Liver 264
White Adipose Tissue 267
Pancreatic Beta Cells 270
Hypothalamus 272
Myocardium 274
Skeletal Muscle 277
Conclusion 280
Acknowledgments 280
References 281
15 Pancreatic Beta Cell Autophagy and Islet Transplantation 284
Introduction 285
Crinophagy in Beta Cells 285
Autophagy and Beta Cell Function 285
Induction of Autophagy in MIN6 Cells and in Human Islets 286
Fatty Acids, Beta Cell Autophagy, and Lipotoxicity 287
Beta Cell Autophagy in Diabetes 288
CrossTalk between Autophagy and Apoptosis 288
Autophagy in the Islet Transplantation Setting 289
Hypoxia and Autophagy 290
Targeting Autophagy to Improve the Survival of Transplanted Islets 292
References 293
16 Autophagy Guards Against Immunosuppression and Renal Ischemia-Reperfusion Injury in Renal Transplantation 296
Introduction 297
Basal Autophagic Activity 297
Autophagy and I/R Injury 299
Protective Mechanisms 300
Autophagy and ImmunosuppresSants 301
Autophagy and Metabolic Stress 302
Discussion 303
References 304
17 When the Good Turns Bad: Challenges in the Targeting of Autophagy in Neurodegenerative Diseases 306
Introduction 307
Briefly: The Highly Regulated Autophagy Pathway 307
Autophagy Modulation in Neurodegenerative Diseases 309
Autophagy Impairment and Neurodegeneration: When the Good Becomes Bad 311
Defects of Autophagy Induction 311
Alterations in Nucleation/Autophagosome Formation 314
Vesicle Expansion Perturbations 314
Abnormal Cargo Recognition 315
Crossroads of Autophagy and Endocytosis 316
Autophagosome Clearance Alterations 317
Conclusions and Perspectives 317
Acknowledgments 318
References 318
18 The a-Tubulin Deacetylase HDAC6 in Aggresome Formation and Autophagy: Implications for Neurodegeneration 320
Introduction 321
Cytoskeletal Proteins as Targets for the Deacetylase Functions of HDAC6 322
The Role of HDAC6 in Aggresome Formation and Autophagy 323
Aggresome Formation and HDAC6 323
HDAC6 and Autophagy 325
HDAC6 and Heat Shock Responses 325
HDAC6 and Neurodegeneration 326
Acknowledgments 327
References 327
Index 330
Introduction to Autophagy
Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, Volume 5
M.A. Hayat
Autophagy plays a direct or indirect role in health and disease. A simplified definition of autophagy is that it is an exceedingly complex process which degrades modified, superfluous (surplus) or damaged cellular macromolecules and whole organelles using hydrolytic enzymes in the lysosomes. It consists of sequential steps of induction of autophagy, formation of autophagosome precursor, formation of autophagosomes, fusion between autophagosome and lysosome, degradation of cargo contents, efflux transportation of degraded products to the cytoplasm, and lysosome reformation.
This chapter discusses specific functions of autophagy, the process of autophagy, major types of autophagy, influences on autophagy, and the role of autophagy in disease, immunity, and defense.
Keywords
Autophagy; aging; disease; apoptosis; lysosomes
Outline
Specific Functions of Autophagy (A Summary) 4
Autophagy in Normal Mammalian Cells 4
Endoplasmic Reticulum Stress and Autophagy 5
Chaperone-Mediated Autophagy 7
Autophagic Lysosome Reformation 9
Protein Degradation Systems 11
Beclin 1 11
Non-Autophagic Functions of Autophagy-Related Proteins 12
Microtubule-Associated Protein Light Chain 3 13
Reactive Oxygen Species (ROS) 14
Mammalian Target of Rapamycin (mTOR) 14
Role of Autophagy in Tumorigenesis and Cancer 15
Role of Autophagy in Immunity 17
Role of Autophagy in Viral Defense and Replication 19
Role of Autophagy in Intracellular Bacterial Infection 20
Role of Autophagy in Heart Disease 21
Role of Autophagy in Neurodegenerative Diseases 22
Cross-Talk Between Autophagy and Apoptosis 24
Autophagy and Ubiquitination 28
Aggresome: Ubiquitin Proteasome and Autophagy Systems 29
Mitochondrial Fusion and Fission 30
Allophagy 31
Glycophagy 32
Lipophagy 33
Mitophagy 35
Nucleophagy 36
Pexophagy 37
Ribophagy 39
Xenophagy 40
Zymophagy 40
References 41
Introduction
Aging has so permeated our lives that it cannot be stopped, but it can be delayed. Under the circumstances, time is our only friend. Because the aging process is accompanied by disability and disease (for example, Alzheimer’s and Parkinson’s conditions) and cannot be prevented, it seems that slow aging is the only way to have a healthy longer life. In general, aging can be slowed down by not smoking or chewing tobacco, by preventing or minimizing perpetual stress (anger, competition), by abstinence from alcoholic beverages, by regular exercise, and by having a healthy diet. There is no doubt that regular physical activity is associated with a reduced risk of mortality and contributes to the primary and secondary prevention of many types of diseases. Discipline is required to attain this goal.
Regarding the role of a healthy diet, a caloric restriction induces autophagy that counteracts the development of age-related diseases and aging itself. On the other hand, autophagy is inhibited by high glucose and insulin-induced P13K signaling via Akt and mTOR. Based on its fundamental roles in these and other disease processes’ prevention and therapy, autophagy has emerged as a potential target for disease.
Unfortunately, inevitable death rules our lives, and a group of abnormal cells plays a part in it. Safe disposal of cellular debris is crucial to keep us alive and healthy. Our body uses autophagy and apoptosis as clearing mechanisms to eliminate malfunctioning, aged, damaged, excessive, and/or pathogen-infected cell debris that might otherwise be harmful/autoimmunogenic. However, if such a clearing process becomes uncontrollable, it can instead be deleterious. For example, deficits in protein clearance in brain cells because of dysfunctional autophagy may lead to dementia. Autophagy can also promote cell death through excessive self-digestion and degradation of essential cellular constituents.
Humans and other mammals with long lifespans unfortunately have to face the problem of the accumulation of somatic mutations over time. Although most of the mutations are benign and only some lead to disease, there are too many of them. Cancer is one of these major diseases, and is caused by a combination of somatic genetic alterations in a single cell, followed by uncontrolled cell growth and proliferation. Even a single germline deletion of or mutation in a tumor suppressor gene (e.g., p53) predisposes an individual to cancer. It is apparent that nature tries to ensure the longevity of the individual by providing tumor suppressor genes and other protective mechanisms. Autophagy (Beclin 1 gene) is one of these mechanisms that plays an important role in influencing the aging process.
Autophagy research is in an explosive phase, driven by a relatively new awareness of the enormously significant role it plays in health and disease, including cancer, other pathologies, inflammation, immunity, infection, and aging. The term autophagy (auto phagin, from the Greek meaning self-eating) refers to a phenomenon in which cytoplasmic components are delivered to the lysosomes for bulk or selective degradation under the lysosomes’ distinct intracellular and extracellular milieu. This term was first coined by de Duve over 46 years ago (Deter and de Duve, 1967), based on the observed degradation of mitochondria and other intracellular structures within lysosomes of rat liver perfused with the pancreatic hormone glucagon.
Over the past two decades an astonishing advance has been made in the understanding of the molecular mechanisms involved in the degradation of intracellular proteins in yeast vacuoles and the lysosomal compartment in mammalian cells. Advances in genome-scale approaches and computational tools have presented opportunities to explore the broader context in which autophagy is regulated at the systems level.
A simplified definition of autophagy is that it is an exceedingly complex process which degrades modified, superfluous (surplus), or damaged cellular macromolecules and whole organelles using hydrolytic enzymes in the lysosomes. Autophagy can be defined in more detail as a regulated process of degradation and recycling of cellular constituents participating in organelle turnover, resulting in the bioenergetic management of starvation. This definition, however, still represents only some of the numerous roles played by the autophagic machinery in mammals; most of the autophagic functions are listed later in this chapter.
Autophagy plays a constitutive and basally active role in the quality control of proteins and organelles, and is associated with either cell survival or cell death. Stress-responsive autophagy can enable adaptation and promote cell survival, whereas in certain models, autophagy has also been associated with cell death, representing either a failed attempt at survival or a mechanism that supports cell and tissue degradation. Autophagy prevents the accumulation of random molecular damage in long-lived structures, particularly mitochondria, and more generally provides a means to reallocate cellular resources from one biochemical pathway to another. Consequently, it is upregulated in conditions where a cell is responding to stress signals, such as starvation, oxidative stress, and exercise-induced adaptation. The balance between protein and lipid biosynthesis, and their eventual degradation and resynthesis, is one critical component of cellular health.
Degradation and recycling of macromolecules via autophagy provides a source of building blocks (amino acids, fatty acids, sugars) that allow temporal adaptation of cells to adverse conditions. In addition to recycling, autophagy is required for the degradation of damaged or toxic material that can be generated as a result of ROS accumulation during oxidative stress. The mitochondrial electron transport chain and the peroxisomes are primary sources of ROS production in most eukaryotes.
Specific Functions of Autophagy (A Summary)
Autophagy plays a direct or indirect role in health and disease, including, among others, control of embryonic and early postnatal development; tissue homeostasis (protein and cell organelle turnover); mitochondrial quality control; protection of cells from stresses; survival response to nutrient deprivation; cellular survival or physiological cell death...
| Erscheint lt. Verlag | 26.9.2014 |
|---|---|
| Sprache | englisch |
| Themenwelt | Sachbuch/Ratgeber ► Gesundheit / Leben / Psychologie |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Dermatologie | |
| Studium ► 1. Studienabschnitt (Vorklinik) ► Histologie / Embryologie | |
| Studium ► 2. Studienabschnitt (Klinik) ► Pathologie | |
| Studium ► Querschnittsbereiche ► Infektiologie / Immunologie | |
| Naturwissenschaften ► Biologie ► Zellbiologie | |
| Technik | |
| ISBN-10 | 0-12-801054-1 / 0128010541 |
| ISBN-13 | 978-0-12-801054-9 / 9780128010549 |
| Haben Sie eine Frage zum Produkt? |
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