Benign prostate hyperplasia (BPH) and prostate cancer are two major health problems of men in this country. The androgen receptor is critical for both growth and survival of benign and cancerous prostate cells. Mitogenic effects of androgens are mediated in part by androgen-induced increases in proliferation-promoting proteins, such as proliferating cell nuclear antigen (PCNA), cyclin-dependent kinases 2 and 4, as well as decreases in cell cycle inhibitors, such as cyclin-dependent kinase inhibitor p16 ink4a. Although the mechanistic details of the anti-apoptotic effects of androgens are far from elucidated, progress has been made recently in our laboratory and others. We and others have demonstrated that androgens act as survival factors by antagonizing the function of the tumor suppressor gene PTEN. An effector downstream of PTEN, the forkhead transcription factor FKHR, plays a critical role in apoptosis by inducing the transcription of proapoptotic genes. We and others have shown that forced expression of FKHR induces apoptosis in prostate cancer cells, suggesting that FKHR is a critical pro-apoptotic player in prostate cancer cells. Our data have demonstrated that androgens abrogate FKHR-induced death of prostate cancer cells. Moreover, we have demonstrated that androgens inhibit the activity of FKHR by regulating lysosome-mediated proteolysis of this protein. Thus, we hypothesize that androgens antagonize death of prostate cells at least in part via their inhibitory effects on the pro-apoptotic function of FKHR. To test this hypothesis, we propose to (1) determine the proteolytic cleavage site in the FKHR protein; (2) identify the androgen-regulated protease(s) that cleaves FKHR; (3) determine whether blockage of the effect of androgens on FKHR favors the death of prostate cancer cells. These findings should enhance our understanding of the action of androgens on growth and survival of both normal and malignant prostate cells. Also, identification of such novel proteins will enable us to better manipulate androgen-regulated events in BPH and prostate cancer.
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