Investigating the Function and Regulation of Prostate Apoptosis Response-4 in Cancer PDF Download
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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: 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: 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: United States. Public Health Service. Office of the Surgeon General
Publisher:
ISBN:
Category : Government publications
Languages : en
Pages : 728
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Book Description
This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.
Author: Manfred Wirth
Publisher: Walter de Gruyter
ISBN: 3110807270
Category : Medical
Languages : en
Pages : 220
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Book Description
Author: Anne Le
Publisher: Springer
ISBN: 331977736X
Category : Medical
Languages : en
Pages : 186
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Book Description
Genetic alterations in cancer, in addition to being the fundamental drivers of tumorigenesis, can give rise to a variety of metabolic adaptations that allow cancer cells to survive and proliferate in diverse tumor microenvironments. This metabolic flexibility is different from normal cellular metabolic processes and leads to heterogeneity in cancer metabolism within the same cancer type or even within the same tumor. In this book, we delve into the complexity and diversity of cancer metabolism, and highlight how understanding the heterogeneity of cancer metabolism is fundamental to the development of effective metabolism-based therapeutic strategies. Deciphering how cancer cells utilize various nutrient resources will enable clinicians and researchers to pair specific chemotherapeutic agents with patients who are most likely to respond with positive outcomes, allowing for more cost-effective and personalized cancer therapeutic strategies.
Author: Vivek M. Rangnekar
Publisher: Springer Nature
ISBN: 3030735729
Category : Medical
Languages : en
Pages : 328
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Book Description
Par-4 is a tumor suppressor protein first discovered and identified in 1993 by Dr. Vivek Rangnekar’s laboratory in prostate cancer cells undergoing apoptosis. Par-4 (later also known as PAWR) is a naturally occurring tumor suppressor. Studies have indicated that Par-4 selectively induces apoptosis in cancer cells while leaving normal, healthy, cells unaffected. Mechanisms contributing to the cancer-selective action of Par-4 have been associated with protein kinase A activation of intracellular Par-4 in cancer cells or GRP78 expression primarily on the surface of cancer cells. Par-4 is downregulated, inactivated or mutated in diverse cancers. This first of two volumes will be the first on the market on the topic of Par-4, and will provide the opportunity for researchers to discuss the future direction of studies, broaden the scope of research, and contribute a more complete understanding of the molecule’s structural features, key functional domains, regulation and relevant basic and clinical/translational facets.
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: Kerry S. Courneya
Publisher: Springer Science & Business Media
ISBN: 3642042317
Category : Medical
Languages : en
Pages : 389
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Book Description
This book explores in depth the relation between physical activity and cancer control, including primary prevention, coping with treatments, recovery after treatments, long-term survivorship, secondary prevention, and survival. The first part of the book presents the most recent research on the impact of physical activity in preventing a range of cancers. In the second part, the association between physical activity and cancer survivorship is addressed. The effects of physical activity on supportive care endpoints (e.g., quality of life, fatigue, physical functioning) and disease endpoints (e.g., biomarkers, recurrence, survival) are carefully analyzed. In addition, the determinants of physical activity in cancer survivors are discussed, and behavior change strategies for increasing physical activity in cancer survivors are appraised. The final part of the book is devoted to special topics, including the relation of physical activity to pediatric cancer survivorship and to palliative cancer care.
Author: Rahul Jandial
Publisher: CRC Press
ISBN: 9781587066597
Category : Medical
Languages : en
Pages : 312
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Book Description
Most cancer deaths are a result of metastasis. The spread of a primary tumor to colonize neighboring and distant organs is the relentless endgame that defines the neoplastic process. Patients who have been diagnosed with cancer are treated to prevent both the recurrence of the tumor at the site of origin and metastasis that would re-stage them as advanced stage IV cancer. Historically and still with some types of cancer, stage IV is perceived by patients as “terminal.” Fortunately, recent molecular therapies have extended the lives of patients with advanced cancer and reassuringly people living with metastatic disease increasingly visit our clinics. What is the path forward? Given that the consilience of science and medicine is a dynamic art from which therapies arise, it would be misguided to consider any single work adequate at capturing the horizon for research. So with humility we constructed this text as primer for scientists. It begins with a broad introduction to the clinical management of common cancers. This is intended to serve as a foundation for investigators to consider when developing basic science hypotheses. Unquestionably, medical and surgical care of cancer patients reveals biology and dictates how novel therapeutics will ultimately be evaluated in clinical trials. The second section of this text offers provocative and evolving insights that underscore the breadth of science involved in the elucidation of cancer metastasis biology. The text concludes with information that integrates scientific and clinical foundations to highlight translational research. This book serves as a framework for scientists to conceptualize clinical and translational knowledge on the complexity of disease that is metastatic cancer.
Author: Simona Maria Monti
Publisher:
ISBN: 9783036510293
Category :
Languages : en
Pages : 196
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Book Description
It is now clearly established that some proteins or protein regions are devoid of any stable secondary and/or tertiary structure under physiological conditions, but still possess fundamental biological functions. These intrinsically disordered proteins (IDPs) or regions (IDRs) have peculiar features due to their plasticity such as the capacity to bind their biological targets with high specificity and low affinity, and the possibility of interaction with numerous partners. A correlation between intrinsic disorder and various human diseases such as cancer, diabetes, amyloidoses and neurodegenerative diseases is now evident, highlighting the great importance of the topic. In this volume, we have collected recent high-quality research about IDPs and human diseases. We have selected nine papers which deal with a wide range of topics, from neurodegenerative disease to cancer, from IDR-mediated interactions to bioinformatics tools, all related to IDP peculiar features. Recent advances in the IDPs/IDRs issue are here presented, contributing to the progress of knowledge of the intrinsic disorder field in human disease.
