Androgenic Inactivation of FKHR in Prostate Cancer

描述(由申请人提供)： 良性前列腺增生(BPH)和前列腺癌是这个国家男性的两大健康问题。雄激素受体对良性和癌性前列腺细胞的生长和存活都是至关重要的。雄激素的促有丝分裂作用部分是通过雄激素诱导的促增殖蛋白的增加，如增殖细胞核抗原(增殖细胞核抗原)、细胞周期蛋白依赖性激酶2和4的增加，以及细胞周期抑制物的减少，如细胞周期蛋白依赖性激酶抑制剂p16 INK4A的减少。虽然雄激素抗细胞凋亡作用的机制细节还远未阐明，但我们的实验室和其他实验室最近已经取得了进展。我们和其他人已经证明，雄激素通过拮抗肿瘤抑制基因PTEN的功能而发挥生存因子的作用。作为PTEN下游的效应因子，叉头转录因子FKHR通过诱导促凋亡基因的转录在细胞凋亡中发挥关键作用。我们和其他人已经证明了FKHR的强制表达诱导了前列腺癌细胞的凋亡，这表明FKHR在前列腺癌细胞中是一个关键的促凋亡角色。我们的数据表明，雄激素可以消除FKHR诱导的前列腺癌细胞死亡。此外，我们还证明了雄激素通过调节溶酶体介导的蛋白分解来抑制FKHR的活性。因此，我们假设雄激素至少部分地通过抑制FKHR的促凋亡功能来拮抗前列腺细胞的死亡。为了验证这一假设，我们建议(1)确定FKHR蛋白中的蛋白水解性切割位置；(2)确定切割FKHR的雄激素调节的蛋白酶(S)；(3)确定阻断雄激素对FKHR的影响是否有利于前列腺癌细胞的死亡。这些发现将加强我们对雄激素对正常和恶性前列腺细胞生长和存活的作用的理解。此外，识别这些新的蛋白质将使我们能够更好地操纵BPH和前列腺癌中雄激素调节的事件。

DESCRIPTION (provided by applicant): 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.