In normal prostate cells, and at an early stage of prostate cancer, the growth of the cells is iandrogen-dependent, and can be effectively suppressed by hormonal ablation. Tumor cells l invariably become androgen resistant, however. The molecular mechanisms by which prostate cancer cells become insensitive to hormonal ablation are unknown, as yet, and several factors may be involved. Prohibitin is a potential tumor suppressor with anti-proliferative activity and regulates the progression of cells in the GI/S transition through its effects on E2F transcriptional activity. Our preliminary studies strongly suggest that prohibitin participates in the regulation of prostate cancer cell proliferation, and that androgen withdrawal or antagonists target (and require) the prohibitin/E2F axis to suppress prostate cancer cell growth. Our proposed studies will define the role of prohibitin in the response of prostate cancers to androgen withdrawal/antagonists. We will test the hypothesis that prohibitin, through its effects on the E2F transcription factors, is required for the antiproliferative effects of androgen withdrawal/antagonists on prostate cancer cells.
Specific Aims i nclude: 1) Determine the mechanism of androgen withdrawal/antagonist-induced growth repression; and, 2) Determine the regulation of prohibitin activity by androgen antagonists. We will determine the necessity of prohibitin in androgen antagonist-mediated growth arrest, using multiple prostate cell lines and diverse androgen antagonists, through colony-formation assays, cell cycle progression analyses and apoptosis analyses. We will determine the function of prohibitin in androgen antagonist-mediated transcriptional repression of E2F. We will evaluate the effects of androgen antagonists on expression of the prohibitin gene and protein and on the interactions of prohibitin and E2F. We will determine the necessity of prohibitin co-repressors, HDAC and Brm/Brg-1, in androgen withdrawal/antagonist-mediated repression of E2F transcriptional activity and growth. Our proposed studies will define a novel signaling pathway required for response to androgen withdrawal/ antagonists in prostate cells, thereby identifying new molecular targets in prostate cancer.
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