Investigating the Function and Regulation of Prostate Apoptosis Response-4 in Cancer PDF Download

Author: Jeffrey Nguyen
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Languages : en
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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.