Prostate cancer is the 2nd leading cause of cancer death in American men, mainly due to therapy-resistance in the advanced stage, androgen... Show moreProstate cancer is the 2nd leading cause of cancer death in American men, mainly due to therapy-resistance in the advanced stage, androgen-independent prostate cancer (AIPCa). One major defect is that the cancer cells are insensitive to apoptosis induced by androgen ablation, chemotherapy or radiation therapy. However, the underline molecular mechanism still remains unclear. In this thesis, we focused on cell death signaling regulation in the development of AIPCa cells. We first show that up-regulation of Bcl-2, an anti-apoptotic oncogene, is required for the transition of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage. Knockdown Bcl-2 impairs the transition process and blocks androgen-independent prostate tumor formation in vivo. Second, we show that Androgen-receptor (AR), which is generally considered as a survival factor in prostate cancer, promotes stress-induced apoptosis in AIPCa cells. AR promotes apoptosis through augmenting the mitochondrial translocation of Bax, a pro-death family member of Bcl-2. Finally, we show that AR can execute both pro-death and pro-survival events in same AIPCa cells. The AR pro-survival role is transcription-dependent, while its pro-death activity is transcription-independent. Interestingly, the AR exerts both functions through regulating p21 and JNK signaling pathways. These findings will help us to understand the dynamic survival signaling process in the development and progression of AIPCa. The key molecules identified here also provides potential therapeutic targets for the treatment of prostate cancer. Ph.D. in Biology, May 2012 Show less
