Regulatory Pathways In Prostate Cancer

Download or read book Regulatory Pathways in Prostate Cancer written by and published by . This book was released on 2009 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate carcinoma (CaP) is the most diagnosed cancer and the second leading cause of cancer-related deaths in American males. Radiation therapy is one of the few treatments for localized CaP. Although it is initially effective, tumor recurrences are common. Therefore, the curative potential of radiation therapy has yet to be improved. My work presented in the chapter II demonstrates that modulation of p53-dependent DNA repair gene p53R2 by RNA interference sensitize a subset of prostate cancer cells to ionizing radiation. The underline mechanisms include the impairment of DNA repair, retardation of cell cycle arrest and activation of p53-dependent apoptosis pathways. For advanced CaP, androgen ablation therapy is effective initially, but eventually, hormone-refractory tumors emerge. Hence, a better understanding of the mechanisms leading to androgen independence and how it is sustained is important in managing the disease. Our lab has previously reported a novel mechanism of androgen independence: calpain 2 cleaves the androgen receptor (AR) into an androgen-independent low molecular weight (LMW) isoform. In the Chapter III presented in the dissertation, we demonstrate that activated MAPK kinase signaling pathway coupled with increased calpain 2/calpastatin rations promotes the expression of the LMW-AR in prostate cancer cells and tumor tissues. Furthermore, the study presented in the Chapter IV characterizes the transcriptional regulation and chromosomal binding features of the full-length (FL) and LWM-AR in two related androgen independent prostate cancer cell lines. Novel AR direct target genes are also reported. These studies provide the insight into the action of FL- and LMW-AR in conferring androgen-independent growth of CaP. Prostate tumor cells employ multiple pathways to proliferate and thrive in castrate levels of androgen. Deregulation of E2F/Rb pathway has been shown to contribute to prostate tumorigenesis and androgen independent growth. Our preliminary study presented in the Chapter V shows that E2F3 is over-expressed in transformed prostate cancer cells and modulation of E2F3 by RNA interference affects their proliferation and apoptotic responses. Several novel E2F3 regulated genes have been identified that play roles in the progression of CaP. The results warrant further investigation of the role of E2F3 in prostate tumorigenesis and androgen independent growth.