Androgenic Inactivation of FKHR in Prostate Cancer

前列腺癌中 FKHR 的雄激素失活

• 批准号: 6683490
• 负责人: DONALD J. TINDALL
• 金额: $ 25.55万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6683490
• 关键词: androgens; apoptosis; benign prostate hyperplasia; cell growth regulation; cytotoxicity; endopeptidases; hormone regulation /control mechanism; mass spectrometry; prostate neoplasms; protein purification; protein sequence; protein structure function; proteolysis; site directed mutagenesis; tissue /cell culture; transcription factor

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.

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。雄激素受体对于良性和癌性前列腺细胞的生长和存活至关重要。雄激素的有丝分裂作用部分是通过雄激素诱导的增殖促进蛋白（例如增殖细胞核抗原（PCNA）、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剂（例如细胞周期蛋白依赖性激酶抑制剂 p16 ink4a）的减少来介导的。尽管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取得进展。我们和其他人已经证明雄激素通过拮抗肿瘤抑制基因 PTEN 的功能而充当生存因子。 PTEN 下游的效应子叉头转录因子 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，FKHR 的强制表达会诱导前列腺癌细胞凋亡，这表明 FKHR 是前列腺癌细胞中关键的促凋亡因子。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，我们已经证明雄激素通过调节溶酶体介导的 FKHR 蛋白的蛋白水解来抑制 FKHR 的活性。因此，我们假设雄激素至少部分通过其对 FKHR 促凋亡功能的抑制作用来拮抗前列腺细胞的死亡。为了检验这一假设，我们建议 (1) 确定 FKHR 蛋白中的蛋白水解切割位点； (2) 鉴定裂解 FKHR 的雄激素调节蛋白酶； (3)确定阻断雄激素对FKHR的作用是否有利于前列腺癌细胞的死亡。这些发现应该增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，鉴定此类新型蛋白质将使我们能够更好地操纵前列腺增生症和前列腺癌中雄激素调节的事件。