Novel Role of Prostate Apoptosis Response-4 Tumor Suppressor in B-cell Chronic Lymphocytic Leukemia PDF Download
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Author: Mary Kathryn McKenna
Publisher:
ISBN:
Category :
Languages : en
Pages : 196
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Book Description
Author: Mary Kathryn McKenna
Publisher:
ISBN:
Category :
Languages : en
Pages : 196
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Book Description
Author: Jeffrey Nguyen
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
Cancer is a disease where normal cells proliferate uncontrollably, which can ultimately lead to significant morbidity and death. The aggressiveness and mortality of cancers vary by type: certain cancers respond well to treatment, such as pediatric leukemias, whereas pancreatic cancer and glioblastoma have a high mortality and low five-year survival. In an effort to improve current cancer therapies, I focus on elucidating the function and regulation of prostate apoptosis response-4 (Par-4) in various cancers. Par-4 is a tumor-suppressor that has been shown to induce cancer cell selective apoptosis and to sensitize cancer cells to apoptotic stimuli, such as chemotherapeutics and radiation, and therefore has therapeutic potential. In the first part of this work, I focused on studying the effect of Par-4 on cell migration, invasion, and the epithelial-mesenchymal transition in colon cancer cells. I found that ectopic expression of Par-4 inhibited both cell migration and cell invasion, while knocking down Par-4 promoted cell migration in SW480 and SW620 colon cancer cells. In addition, I found that Par-4 overexpression appeared to induce a mesenchymal-epithelial transition in SW620 cells. In the second part of this work, I sought to identify novel regulators of Par-4 and elucidate the mechanism of regulation. I identified Trim21 as a novel binding partner in colon cancer cells, and show that Trim21 overexpression in the presence of cisplatin downregulates Par-4 in colon and pancreatic cancer cell lines, and show that modulating levels of Trim21 and Par-4 affects the sensitivity of cancer cells to cisplatin. Finally, I demonstrate that Trim21 mRNA levels correlate with survival in pancreatic cancer patients, with lower Trim21 levels correlating with increased overall survival and disease-free survival and high Trim21 levels correlating with reduced disease-free survival. In the third part of this work, I sought to determine whether Par-4 could enhance the effectiveness of chemotherapeutics and small molecule drugs. I chose to focus on glioma due to the lack of effective therapeutics. I show that ectopic Par-4 expression alone is sufficient to reduce cell viability and to induce apoptosis in glioma cell lines, A172 and SNB19. Furthermore, I demonstrate that Par-4 transfected glioma cells are sensitized to 5-fluorouracil and ISC-4. Taken together, the results presented in this dissertation suggest novel roles and regulatory mechanisms of Par-4 in cancer, and provide rationale for its use in cancer treatment; as well as suggesting a novel prognostic marker for pancreatic cancer.
Author: Joseph Thomas Greene
Publisher:
ISBN:
Category : B cells
Languages : en
Pages : 132
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Book Description
The Eμ-TCL1 mouse is a B cell leukemia model commonly used to test the efficacy of experimental therapeutics and interrogate the functions of oncogenes and tumor suppressors. The CLL-like disease in this mouse shares similar pathology and molecular etiology with the human variant. We therefore hypothesized that overexpression of the human isoform of Par-4 in the B cells of this mouse would impede disease progression through either an anti-proliferative or pro-apoptotic mechanism. Consistent with this hypothesis, results indicated that B cell-specific overexpression of human Par-4 reduced the rate of T Cell Leukemia/Lymphoma 1 (TCL1)-induced leukemogenesis. In addition, B cell-specific knockout of endogenous Par-4 increased the rate of TCL1-induced leukemogenesis. Par-4 activity is regulated through a variety of mechanisms, which seem to give it a pleiotropic property. It is generally thought to act as either an anti-proliferative or pro-apoptotic tumor suppressor. In our study, TCL1 mice overexpressing human Par-4 were found to harbor malignant B cell clones that proliferated at reduced rates when compared to their Par-4 wild-type (WT) littermates. This indicated that Par-4 was reducing the expansion of overexpressing cells; which we found interesting, because Par-4 overexpressing mice null for the TCL1 oncogene exhibited no phenotype when examined in various immune response assays.
Author: Vivek M. Rangnekar
Publisher: Springer Nature
ISBN: 3030805581
Category : Medical
Languages : en
Pages : 329
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Book Description
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.
Author: Stuart K. Calderwood
Publisher: Springer Science & Business Media
ISBN: 1402064012
Category : Medical
Languages : en
Pages : 399
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Book Description
Heat shock proteins are emerging as important molecules in the development of cancer and as key targets in cancer therapy. These proteins enhance the growth of cancer cells and protect tumors from treatments such as drugs or surgery. However, new drugs have recently been developed particularly those targeting heat shock protein 90. As heat shock protein 90 functions to stabilize many of the oncogenes and growth promoting proteins in cancer cells, such drugs have broad specificity in many types of cancer cell and offer the possibility of evading the development of resistance through point mutation or use of compensatory pathways. Heat shock proteins have a further property that makes them tempting targets in cancer immunotherapy. These proteins have the ability to induce an inflammatory response when released in tumors and to carry tumor antigens to antigen presenting cells. They have thus become important components of anticancer vaccines. Overall, heat shock proteins are important new targets in molecular cancer therapy and can be approached in a number of contrasting approaches to therapy.
Author: Seamus J. Martin
Publisher: S. Karger AG (Switzerland)
ISBN: 9783805565790
Category : Apoptosis
Languages : en
Pages : 0
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Book Description
The past five years have witnessed an explosion of research efforts in the study of how cells die. This book provides an up-to-date overview of our current knowledge of apoptosis and how discoveries in this area impact on our understanding of cancer. By synthesizing many of the recent developments in this area and placing them in perspective, it fulfills an important need. All the contributions are written by experts in their respective fields. The first two chapters give a basic introduction to the cell death machinery and its role in tumor development and progression; subsequent chapters cover current aspects of apoptosis research, including the involvement of cell cycle-related proteins (e.g. cyclin-dependent kinases) in apoptosis, the role of Bcl-2, Bcr-Abl, Rb, p53 and myc in the regulation of cell death, and apoptosis in the context of specific neoplasms such as cancer of the prostate, kidney, leukemia and neuroblastoma. It is also discussed how insights into the regulation of apoptosis may be exploited for designing new drugs aimed at eliminating malignant cells. Compiling the most recent research results on the relationship between apoptosis and cancer in one handy volume, this book will provide a valuable reference for scientists working in cancer research as well as newcomers to the field.
Author: David A. Frank
Publisher: Springer Science & Business Media
ISBN: 1402073402
Category : Medical
Languages : en
Pages : 358
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Book Description
One of the most exciting areas of cancer research now is the development of agents which can target signal transduction pathways that are activated inappropriately in malignant cells. The understanding of the molecular abnormalities which distinguish malignant cells from their normal counterparts has grown tremendously. This volume summarizes the current research on the role that signal transduction pathways play in the pathogenesis of cancer and how this knowledge may be used to develop the next generation of more effective and less toxic anticancer agents. Series Editor comments: "The biologic behavior of both normal and cancer cells is determined by critical signal transduction pathways. This text provides a comprehensive review of the field. Leading investigators discuss key molecules that may prove to be important diagnostic and/or therapeutic targets."
Author: Jen-Chywan Wang
Publisher: Springer
ISBN: 1493928953
Category : Science
Languages : en
Pages : 387
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Book Description
This timely volume provides a comprehensive overview of glucocorticoids and their role in regulating many aspects of physiology and their use in the treatment of disease. The book is broken into four sections that begin by giving a general introduction to glucocorticoids and a brief history of the field. The second section will discuss the effects of glucocorticoids on metabolism, while the third section will cover the effects of glucocorticoids on key tissues. The final section will discuss general topics, such as animal models in glucocorticoid research and clinical implications of glucocorticoid research. Featuring chapters from leaders in the field, this volume will be of interest to both researchers and clinicians.
Author: Marek Los
Publisher: Springer Science & Business Media
ISBN: 0387236953
Category : Medical
Languages : en
Pages : 411
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Book Description
As our understanding of apoptotic pathway expands, we are coming to realize the great potential of utilizing this pathway to treat diseases such as cancer. The book attempts to review, summarize, and speculate on the apoptotic pathways, how are they regulated and how targeted therapies are being used to treat a wide variety of diseases. Special emphasis is placed on cancer since new treatments either being developed or currently in the clinical setting are showing great promise to increase survival rates for cancer patients. Chapters will address the biology behind regulating the apoptotic pathways and what goes wrong in disease states whereas other chapters will concentrate on new therapies targeting apoptotic pathways. The reader by the end of the book should have greater insight into the understanding and utilization of apoptotic pathways to fight diseases such as cancer.
Author: Toshiyuki Fukada
Publisher: Springer Nature
ISBN: 9811505578
Category : Medical
Languages : en
Pages : 412
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Book Description
This book, now in an extensively revised second edition, describes the crucial role of zinc signaling in biological processes on a molecular and physiological basis. Global leaders in the field review the latest knowledge, including the very significant advances in understanding that have been achieved since publication of the first edition. Detailed information is provided on all the essentials of zinc signaling, covering molecular aspects and the roles of zinc transporters, the zinc sensing receptor, and metallothioneins. Detection techniques for zinc signals, involving genetically encoded and chemical probes, are also described. The critical contributions of the zinc signal in maintaining health and the adverse consequences of any imbalance in the signal are then thoroughly addressed. Here, readers will find up-to-date information on the significance of the zinc signal in a wide range of conditions, including cardiovascular disorders, neurodegenerative diseases, diabetes, autoimmune diseases, inflammatory conditions, skin disease, osteoarthritis, and cancer. The book will be of value for researchers, clinicians, and advanced students.
