Tumor Suppressor Par-4 : Role in Cancer and Other Diseases

Par-4 is a naturally occurring tumor suppressor. Studies have indicated that overexpression of Par-4 selectively induces apoptosis in cancer cells while leaving normal, health, cells unaffected. Mechanisms contributing to this cancer-selective action of Par-4 have been associated with PKA activation of intracellular Par-4 in cancer cells or GRP78 expression primarily on the surface of cancer cells. On the other hand, endogenous Par-4 sensitizes cells to the action of a broad range of apoptotic inducers acting via the extrinsic and intrinsic pathways. A number of binding partners of Par-4 have been identified and shown to regulate Par-4 function in cancer and other diseases, such as Alzheimer’s and major depression. Recent studies have recognized a number of natural products, dietary supplements, synthetic molecules and FDA-approved drugs that induce the secretion of Par-4 protein to cause apoptosis in primary or metastatic tumors, one of which is in clinical trials. More than 50 different laboratories worldwide are involved in Par-4 based research of this unique protein that has progressed from the bench to clinical trials. This second, companion volume will provide a comprehensive overview of Par-4’s role in cancer and other diseases. Chapters are written by leading researchers, and will be useful for a broad audience across the scientific community, particularly students and trainees, who are the next generation of scientists and clinicians to participate in new studies and discoveries on Par-4. Preface Contents Role of Par-4 in EMT 1 Introduction 1.1 Epithelial to Mesenchymal Transition (EMT) 1.2 Regulators of EMT 1.2.1 TGF-β Signaling Pathway 1.2.2 Wnt Signaling 1.2.3 Notch Signaling 1.2.4 HIF-1α Signaling 1.2.5 Integrin Signaling 1.2.6 microRNAs 1.3 EMT Markers 1.3.1 Epithelial Markers 1.3.2 Mesenchymal Markers 1.4 EMT Paves the Way for Tumor Metastasis 1.4.1 EMT and Malignant Transformation 1.4.2 Intravasation 1.4.3 Systemic Transport 1.4.4 Tumor Cell Extravasation and EMT 1.4.5 Metastatic Colonization and MET 1.5 EMT Acquisition by Mesenchymal Cells—A Real Challenge in the Development of Cancer Therapeutics 2 Par-4 Emerges out as a Prospective EMT Modulatory Protein 2.1 Structural Aspects of Par-4(SAC Domain) that Link it with EMT 2.2 Regulation of NF-κB Activity by Par-4 2.3 Regulation of EMT-Associated Transcription Factors by Par-4 2.4 Role of Par-4 in Regulation of Cytoskeletal and ECM Remodeling 2.5 Par-4 and Destabilization of β-Catenin Pathway 3 New Insights Linking Par-4 and EMT 3.1 Lethal EMT: TGF-β Signaling and Par-4 3.2 BMP and ALK Signaling 3.3 Anti-Metastatic miRNAs and Par-4 4 Conclusion, Limitations, and Future Perspectives References Prostate Apoptosis Response-4 in Inflammation 1 Introduction 2 Diseases Caused by Inflammation 3 Inflammation and Cancer 3.1 Inflammation as an Initiation Factor 3.2 Inflammation as a Factor in Cancer Progression and Metastasis 4 Non-Steroidal Anti-Inflammatory Drugs 5 Par-4 and Cancer 6 Par-4 and Inflammation 6.1 Role of Ras in Cancer and Inflammation 6.2 Role of NF-κB 6.3 Role of Bcl-2 6.4 Role of Fas 6.5 Inhibition of Par-4 in Response to Inflammatory Stimuli 6.6 Par-4 as a Mediator of Anti-Inflammatory Drug Action 7 Future Research Directions 8 Conclusions References Par-4 in Chemoresistant Ovarian and Endometrial Cancers 1 Introduction 1.1 Pathogenesis and Molecular Mechanisms of Chemoresistance 1.2 Par-4 in Gynecological Tissues 2 Ovarian Cancer 2.1 Statistics 2.2 Histological, Morphological Subtyping, and Pathogenesis 2.3 Molecular Subtyping 2.4 Current Therapeutic Strategies 3 Endometrial Cancer 3.1 Statistics 3.2 Histological, Morphological Subtyping, and Pathogenesis 3.3 Molecular Subtyping 3.4 Current Therapeutic Strategies 4 Molecular Pathways Responsible for Chemoresistance in Ovarian and Endometrial Cancers and the Place of Par-4 in those Signaling Networks 4.1 The PI3K/Akt/mTOR Axis 4.2 NF-kB 4.3 p53 4.4 Autophagy in Chemoresistance 5 Molecular Determinants of Par-4 Function 5.1 Role and Regulation of Nuclear Par-4 5.2 Post-Translational Regulation of Par-4 6 Conclusion 6.1 The Functional Pleiotropy of Par-4 7 Future Perspective 7.1 Deciphering the Role of Par-4 in Chemoresistance of OC and EC Cells References Regulation and Role of Par-4 in Gastrointestinal Tumors 1 Background 2 Colorectal Cancer 2.1 Background 2.2 Current Treatment of Colorectal Cancers 2.3 Regulation of Par-4 Expression in Colorectal Tumors 2.4 Regulation of Par-4 Activity in Colorectal Tumors 2.5 Par-4 as a Target for Treatment of Colorectal Cancers 3 Par-4 in Cholangiocarcinoma 3.1 Background 3.2 Expression and Activity of Par-4 in Cholangiocarcinoma 4 Par-4 in Stomach Cancer 4.1 Background 4.2 Putative Role of Par-4 in Gastric Cancer 5 Par-4 in Oral Cancers 5.1 Background 5.2 Role of Par-4 in Oral Cancer 6 Par-4 in Other Tumors of the Gastrointestinal Tract 7 Summary References Role of Par-4 in Radiation Sensitivity of Cancer 1 Introduction 2 Radiation-Induced Signaling Pathways 2.1 NF-κB and PAR-4 3 Anti-Apoptotic Proteins and PAR-4 3.1 Bcl-2 and PAR-4 4 RAS Signaling and PAR-4 4.1 K-RAS and PAR-4 5 Cytokines and PAR-4 5.1 Radiation-Induced Cytokines and PAR-4 6 Summary and Future Directions References Prostate Apoptosis Response-4: a Therapeutic Target for Malignant Gliomas 1 Introduction and Classification of Gliomas 2 Etiology, Epidemiology, and Clinical Symptoms 2.1 Etiology 2.2 Epidemiology 2.3 Clinical Symptoms 3 Survival Rate 4 Current Approved Treatment Options for GBM 4.1 Surgery 4.2 Radiation Therapy 4.3 Chemotherapy 4.3.1 Temozolomide (TMZ) 4.3.2 Carmustine and Lomustine 4.3.3 Bevacizumab 4.3.4 Cyclophosphamide 4.4 Tumor-Treating Field 5 Challenges and Unmet Need 6 Cancer Stem Cells/Glioma Stem Cells 7 Tumor Microenvironment (TME) in GBM 7.1 Tumor Vasculature 7.2 Heterogeneity in the Microenvironment of GBM 7.2.1 Cellular Components Glioma Stem Cells Immune Cells 7.2.2 Non-cellular Components Extracellular Matrix (ECM) Interstitial Fluid 8 Epigenetic Alterations 9 Genetic Mutations and Dysregulated Signaling Pathways 9.1 Dysregulated Pathways, Targeted Therapy, and Clinical Results to Date 9.2 Molecularly Targeted Therapies 9.3 Inhibitors of Receptor Tyrosine Kinases (RTKs) 9.4 Epidermal Growth Factor Receptor (EGFR) Inhibitors 9.4.1 Small-Molecule Inhibitors to EGFR 9.4.2 Monoclonal Antibodies to EGFR 9.5 Vascular Endothelial Growth Factor (VEGF) Inhibitors 9.6 Platelet-Derived Growth Factor (PDGF) 9.7 Other RTKs 9.8 Molecular Targeted Therapies for Glioma and Their Therapeutic Role 9.8.1 Targeting Downstream Intracellular Effector Molecules 9.8.2 PI3K/Akt/mTOR Pathway and Potential Clinical Inhibitors 9.8.3 Ras/Raf/Mitogen-Activated Protein Kinase Pathway 9.8.4 Hepatocyte Growth Factor/c-MET Signaling and Potential Clinical Candidates 9.8.5 Immunotherapies 9.8.6 Other Dysregulated Pathways 10 Tumor Suppressors and Par-4 10.1 Tumor Suppressor as a Therapeutic Target for GBM 10.2 p53/RB/CDKN2A 10.3 Par-4 as a Tumor Suppressor 10.3.1 Discovery 10.3.2 Par-4 Protein Structure 10.4 Intrinsic, Cellular, and Secretory Par-4 10.4.1 Intrinsic Par-4 10.4.2 Secretory Par-4 10.5 Expression of Par-4 in Normal Cells/Tissues and in Cancers 10.6 PAR-4 Modulation/Overexpression/Knockdown/Knockout in Animal Models 10.7 PAR-4 Knockout (KO) Models 10.8 Models with Overexpression of Par-4 10.9 Signaling Pathways and regulation of Par-4 10.9.1 PTEN/Akt/mTOR 10.9.2 RAS/Raf/MAPK/ERK 10.9.3 FOXO Pathway 10.9.4 Tumor Suppressor p53 10.9.5 Casein Kinase 2 (CK2) 10.9.6 Protein Kinase a (PKA) 10.9.7 Protein Kinase C (PKC) 10.9.8 Autophagy 10.9.9 Apoptotic Pathway 10.9.10 Senescence 10.9.11 Metastasis 10.9.12 Cytoskeleton Proteins 10.9.13 Metabolic Pathways 10.10 Induction of Par-4 in Normal Cells and Cancer Cells 11 Role of Par-4 in Gliomas 12 The Road Ahead: Future Perspectives References Involvement of Par-4 in Breast Cancer 1 A Brief Overview of Mammary Gland Development, Function, and Maintenance 2 Breast Cancer 3 Role of Par-4 as a Biomarker in Breast Cancer 4 Role of Par-4 in Breast Cancer Proliferation and Apoptosis 5 Par-4 Intra and Extracellular Possible Mechanisms of Action in Breast Cancer 6 Par-4 in Breast Cancer Chemosensitivity 7 Conclusions and Future Perspectives References Role of Par-4 in B-Cell Hematological Malignancies 1 Introduction 2 Par-4 Expression and Function in Immune Cells 3 Par-4 in B-cell Malignancies 4 Intrinsic Role of Par-4 in CLL 4.1 Par-4 Expression in CLL 4.2 BCR-Mediated Par-4 Regulation in CLL 4.3 Role of Par-4 in the Regulation of CLL Growth Kinetics 5 Par-4 in the Tumor Microenvironment 6 Summary and Future Outlook References The Par-4 Tumor Suppressor Protein in TCL1-Induced Leukemogenesis 1 Introduction 1.1 Leukemia 1.2 Par-4 2 Initial Observations in Lymphoid and Myeloid Leukemias 3 Mechanistic Studies 4 Par-4 in the TCL1 Chronic Lymphocytic Leukemia Model 5 Future Work and Prospects for Therapy References Potential of PAR-4 as a Therapeutic Target for Pancreatic Cancer 1 Introduction 2 PAR-4 and Its Significance in Pancreatic Cancer 3 Oncogenic Mutations and PAR-4 4 Regulation and Interaction of PAR-4 with Other Proteins 5 Role of PAR-4 in Pancreatic Cancer Drug Resistance 6 Role of PAR-4 in Epithelial-Mesenchymal Transition (EMT) 7 Chemopreventive Agents as an Inducer of PAR-4 7.1 3,3′-Diindolylmethane 7.2 NGD16 8 Small Molecule Inhibitors and PAR-4 8.1 BCL-2 Inhibitors 8.2 Selective Inhibitor of Nuclear Export (SINE) 9 Targeting PAR-4 in Pancreatic Cancer in Clinical Settings 10 Conclusion and Future Perspectives References Developing Quinoline-based Secretagogues for Prostate Apoptosis Response-4 Protein (Par-4) as Potential Antineoplastic Agents 1 Protein Secretion 2 Small-Molecule Secretagogues 3 Protein Sequestration by Filament Proteins 4 Tumor Suppressors 5 Secretagogues for Par-4 5.1 Introduction 5.2 Synthesis and Evaluation of Potential Secretagogues 5.3 Identification of Target 5.4 Computational Modeling of Secretagogue Binding to Vimentin 5.5 Secretagogue Induction of Apoptosis 5.6 Future Perspectives 5.6.1 Arylquins and Vimentin Structural Studies 5.6.2 Arylquin SAR Development 5.6.3 Arylquins and Metastasis References Recombinant Production and Characterization of Par-4/SAC 1 Recombinant Par-4 or its SAC Domain as a Promising Therapeutic 2 Recombinant Protein Production of Par-4 and SAC 2.1 Protein Expression in Escherichia coli 2.2 Other Potentially Useful Protein Expression Systems 2.3 Protein Expression in Plant 2.4 Protein Expression in a SUMO Fusion System 3 Characterization of Recombinant Par-4/SAC 3.1 In Vitro Anti-Cancer Activity 3.2 In Vivo Anti-Cancer Activity 3.3 Pharmacokinetics 4 Fc-Fusion Protein to Improve the Pharmacokinetic Profile 4.1 Human Neonatal Fc Receptor (FcRn) as a Promising Target to Improve Pharmacological Profile of a Protein Drug 4.2 Fc-Fusion of Par-4 to Generate a New Protein Entity Par-4Ex 4.3 In Vitro Anti-Cancer Activity of Par-4Ex 4.4 Pharmacokinetics of Par-4Ex 4.5 In Vivo Anti-Cancer Activity of Par-4Ex 5 Concluding Remarks: Summary and Future Perspective References Role of PAR-4 in Ceramide-Inducible Effects in Neurodegeneration 1 Ceramide 2 Ceramide as a Key Player in Neurodegeneration 3 Trans-Indirect Effect of Astrocyte-Derived Ceramide and PAR-4 on Neurons 4 Conclusions and Future Perspectives References Par-4 in Neuronal Death and Survival in Alzheimer’s Disease and Other Neurogenerative Diseases 1 Neuronal Cell Death and Survival in Alzheimer’s Disease 1.1 Introduction to Alzheimer’s Disease 1.2 The Amyloid hypothesis of AD 1.3 Genetic Factors in Early-Onset Familial AD 2 Role of Par-4 in Cell Death and Survival in AD and Other Neurodegenerative Diseases 2.1 Initial Evidence for a Role of Par-4 in Neuronal Degeneration 2.2 Par-4 Participates in Neuronal Cell death in a Mouse Model of Alzheimer’s Disease Expressing a Mutant Form of Presenilin-1: Generation and Characterization of PS-1 M146V Mutant Knock-in Mice 2.3 Par-4 Increases Secretion of Aβ 1–42 through a Caspase-Dependent Pathway 2.4 Par-4 Inhibits Secretion of sAPPα Induced by Protein Kinase C Activator PMA 2.5 Disruption of Intracellular Calcium Homeostasis Contributes to the Aberrant APP Processing Induced by Par-4 2.6 Generation and Characterization of Mice Transgenic for Par-4: Par-4 Increases Production of Aβ 1-42 in Hippocampal Neurons In Vivo 2.7 Par-4 Interacts with AICD and Alters AICD-Mediated Transcriptional Activity and Neurodegeneration in AD 2.8 Par-4 Increases BACE1 Cleavage of APP: Effects of RNAi-Mediated Par-4 Gene Silencing 3 AATF Is a Par-4 Interacting Protein that Functions as an Endogenous Negative Regulator of Par-4 Activity in Neurodegeneration 3.1 Specific Interaction between AATF and Par-4 3.2 AATF Interferes with Binding of Par-4 to AICD and Protects against Cell Death Induced by CTFγ57 4 Neuroprotective Actions of Extracellularly Secreted AATF (sAATF) and SAP-12 4.1 AATF Is Secreted Extracellularly 4.2 AATF Is Associated with Cell Surface Receptor TLR-4 4.3 SAP-12 Confers Greater Neuroprotective Potency and Broader Effective Dose Range than the Full-Length AATF 4.4 Extracellular Release of sAATF Is Negatively Regulated by an Intracellular process Involving Binding of AATF by Par-4 5 Par-4 in the Pathogenesis of Other Neurodegenerative Diseases and Neurological Dysfunctions 5.1 Par-4 Is a Synaptic Protein Involved in Pathogenesis of Amyotrophic Lateral Sclerosis 5.2 Par-4 Is Involved in Degeneration of Dopaminergic Neurons in Models of Parkinson’s Disease 5.3 Par-4 as a Molecular Link between Impaired Dopamine Signaling and Depression 6 Future Directions References Par-4-Dependent Apoptosis of Pancreatic Islet β Cells in Type 2 Diabetes 1 Introduction to Type 1 and Type 2 Diabetes 2 Par-4 Induces Apoptosis in Islet β Cells that Is Linked to the Pathogenesis of Diabetes 3 Par-4/TERT Interaction Regulates the Process of Apoptosis in Islet β Cells 4 Par-4, Autophagy Dysfunction, and Islet β-Cell Apoptosis 5 Par-4 and Insulin Resistance 6 Future Perspectives References Role of PRKC Apoptosis WT1 Regulator in Ocular Development and Diseases 1 Introduction 2 Structure of the Human Eye 3 Development of Eye Anterior Segment 4 Disorders Related to Ocular Development 4.1 ASD Disorders Showing both Ocular and Systemic Phenotypes 4.2 ASD Disorders Showing Only Ocular Phenotypes 4.3 Non-ocular Systemic Disorders Having ASD Features 5 PRKC Apoptosis WT1 Regulator (PAWR)/Prostate Apoptotic Response-4 (PAR-4) 6 Regulatory Network of Transcription Factors in Ocular Disease and Development 6.1 Molecular Interaction between PITX2A And FOX Proteins 6.2 Molecular Interaction of PAWR/PAR4 with FOXC Proteins 6.3 PAWR Regulates PITX2, FOXC1, and FOXC2 Function 6.4 PAWR Influences FOXC Activity in a Gene-Specific Manner 6.5 PAWR Influences PITX2 in a Complex Manner 7 PAWR in Ocular Development 8 Dysregulation of PAWR Causes ASD 8.1 Phenotypic Effects of Knockdown of PITX2, FOXC1, and PAWR 8.2 Genetic Interactions among PAWR, PITX2, and FOXC1 9 Future Perspectives References Par-4 in Apoptosis during Human Salivary Gland Development and Tumorigenesis 1 Aspects of Salivary Gland Development—Brief Morphological and Molecular Considerations 2 Apoptosis and Salivary Gland Development 3 Roles of Par-4 in Salivary Gland Tumorigenesis 4 Conclusions and Future Perspectives References Roles for Par-4 in Kidney Pathophysiology 1 Kidney and Kidney Diseases 1.1 Kidney Anatomy and Physiology 1.2 Kidney Diseases and the Pathogenesis 1.3 Genes and Signaling Pathways Commonly Involved in Various Kidney Diseases 2 Par-4 Expression in Kidney 3 Involvement of Par-4 in Kidney Diseases 3.1 Apoptosis in Kidney 3.2 Actin Cytoskeletal Injury 3.3 Par-4 Interacts with the Molecules Implicated in Kidney Pathophysiology 3.3.1 Wilms’ Tumor Suppressor 1 (WT1) 3.3.2 BCL-2 3.3.3 aPKC 3.4 Role of Par-4 in Kidney Diseases 4 Future Directions References Lessons from Mouse Models 1 Par-4 Deletion in 129Sv Background 2 Deletion of C-Terminal Region of Par-4 3 Par-4 Overexpression and Tumor Resistance 4 Secreted Par-4 and Inhibition of Tumor Growth 5 Par-4 Deletion in C57BL/6 Background 6 Effect of Extracellular and Intracellular Par-4 on Tumor Growth 7 Future Perspectives References Par-4 Secretagogues in Clinical Trials 1 Introduction 2 Par-4 as a Secreted Tumor Suppressor 3 CQ and HCQ 4 Rationale for Using Par-4 Secretagogues and Identification of CQ and HCQ as Secretagogues 5 Autophagy Induction by Anti-Malarial Drugs 5.1 What Is Autophagy 5.2 Autophagy and Cancer 5.3 Autophagy Inhibition by Anti-Malaria Drugs 6 Early Phase Clinical Trials in Oncology 7 HCQ Used as a Par-4 Secretagogue and Blocker of Autophagy in Clinical Trials 8 Future Clinical Trials with Par-4 Secretagogues References Par-4 as a Therapeutic Target in Cancer and Other Diseases 1 Salient Features of Par-4 2 Par-4 Gene Therapy in Cancer 3 Effective Utilization of Recombinant Par-4 4 Par-4 Secretagogues 5 Inducers of Par-4 Receptor GRP78 on the Cell Surface 6 Par-4 Expression as an Indicator of Tumor Relapse 7 Approaches to Modulate Par-4 in Neuronal and Other Diseases 8 Conclusions and Future Perspectives References Correction to: Involvement of Par-4 in Breast Cancer Index