Signal Transduction by Androgen in Prostate Cells

前列腺细胞中雄激素的信号转导

• 批准号: 6775945
• 负责人: Douglas V Faller
• 金额: $ 26.49万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6775945
• 关键词: JUN kinase; androgens; apoptosis; biological signal transduction; cell growth regulation; cell proliferation; clinical research; gel mobility shift assay; gene expression; gene mutation; hormone regulation /control mechanism; hormone related neoplasm /cancer; human tissue; inhibitor /antagonist; neoplasm /cancer genetics; neoplastic cell; neoplastic growth; polymerase chain reaction; prostate neoplasms; protein protein interaction; transcription factor; tumor suppressor genes

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 include: 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.

在正常的前列腺细胞，在前列腺癌的早期阶段，细胞的生长为 依赖伊斯特原，可以通过荷尔蒙消融有效抑制。肿瘤细胞 然而，l总是耐雄激素。前列腺的分子机制 到目前为止，癌细胞对荷尔蒙消融不敏感，并且可能涉及几个因素。禁止素是具有抗增殖活性的潜在肿瘤抑制剂，并通过其对E2F转录活性的影响来调节GI/S转变中细胞的进展。我们的初步研究强烈表明，预防素参与前列腺癌细胞增殖的调节，并且雄激素戒断或拮抗剂的目标（并需要）禁止素/E2F轴以抑制前列腺癌细胞的生长。我们提出的研究将定义前列腺癌对雄激素戒断/拮抗剂的反应中禁止素的作用。我们将检验以下假设：通过对E2F转录因子的影响，雄激素戒断/拮抗剂对前列腺癌细胞的抗增殖作用是必需的。具体目的包括：1）确定雄激素戒断/拮抗剂诱导的生长抑制的机制； 2） 确定雄激素拮抗剂对禁止活性的调节。我们将确定 通过菌落形成测定，细胞周期进程分析和凋亡分析，使用多种前列腺细胞系和多样化的雄激素拮抗剂，在雄激素拮抗剂介导的生长中介导的生长停滞的必要性。我们将确定雄激素拮抗剂介导的E2F的转录抑制的禁止素的功能。我们将评估雄激素拮抗剂对禁止素基因和蛋白质的表达以及禁止素和E2F的相互作用的影响。我们将确定在雄激素戒断/拮抗剂介导的E2F转录活性和生长的抑制中，在雄激素戒断/拮抗剂介导的抑制雄激素戒断/拮抗剂介导的抗抑郁素共抑制剂的必要性。我们提出的研究将定义一种对前列腺细胞中雄激素戒断/拮抗剂反应所需的新型信号通路，从而鉴定了前列腺癌中的新分子靶标。