TGF-Beta Signaling Pathways in Prostate Tumorigenesis

说明(申请人提供)：转化生长因子-b(转化生长因子-β) 通过抑制细胞的能力对前列腺生长的负调节作用 促进上皮细胞增殖和诱导细胞凋亡。有证据表明， 在前列腺癌中，上皮转化生长因子-β的表达增加是平行的 由于其膜受体TbetaRI和TbetaRII的表达缺失。这个 拟议研究的长期目标是确定两者之间的相互作用 雄激素轴和转化生长因子-β信号通路在前列腺癌发生中的作用。 我们最近的研究表明，恢复基因的表达 人前列腺癌细胞LNCaP中的功能性TbetaRII受体 对转化生长因子-β耐药，导致转化生长因子-β敏感和抑制 通过细胞周期停滞和细胞凋亡诱导的致瘤生长。在这 建议我们使用激素敏感型转化生长因子-β反应模型 以探讨前列腺癌的分子机制 转化生长因子-β信号通路功能障碍在前列腺癌发生中的作用具体而言 目的1我们将确定雄激素影响 转化生长因子β对前列腺癌细胞生长的影响及其与细胞周期调控的关系 (CDK抑制剂)和细胞凋亡诱导(半胱氨酸氨基转移酶、bcl2)。的影响 雄激素对转化生长因子-β介导的小鼠体内致瘤生长的抑制作用 LNCaP TbetaRII细胞将通过原位注射进行测定。在……里面 特异靶2：采用基因转染法和免疫共沉淀技术 将研究Smad细胞内效应器的功能参与 转化生长因子-β在将细胞凋亡信号传导至细胞核中的作用。具体而言 目的3雄激素受体(AR)与转化生长因子-β信号的相互作用 LNCaP TbetaRII前列腺细胞中的通路将用 免疫沉淀分析。这些研究将确定：a)雄激素 导致前列腺癌细胞内转化生长因子-β信号转导功能受损； 和b)受体后细胞内介质缺陷的意义 转化生长因子-β信号，Smads，在激素抵抗的发展中 前列腺癌。

DESCRIPTION (provided by applicant):Transforming growth factor-b (TGF-beta) is a negative regulator of prostate growth via its ability to inhibit cell proliferation and induce apoptosis in epithelial cells. Evidence indicates that in prostate cancer an increase in epithelial TGF-beta expression is paralleled by loss of expression of its membrane receptors TbetaRI and TbetaRII. The long-term goal of the proposed studies is to identify the interplay between the androgen axis and TGF-beta signaling pathways during prostate tumorigenesis. Our recent studies demonstrated that restoration of expression of the functional TbetaRII receptor in human prostate cancer cells LNCaP that are resistant to TGF-beta, leads to TGF-beta sensitivity and suppression of tumorigenic growth via cell cycle arrest and apoptosis induction. In this proposal we will use this model of hormone-sensitive TGF-beta responsive prostate cancer cells to explore the molecular mechanism underlying the dysfunctional TGF-beta signaling pathway in prostate tumorigenesis. In Specific Aim 1 we will determine the ability of androgens to affect the action of TGF-beta on prostate cancer cell growth as linked to deregulation of cell cycle (cdk inhibitors) and apoptosis induction (caspases, bcl-2). The effect of androgens on TGF-beta mediated suppression of in vivo tumorigenic growth of LNCaP TbetaRII cells will be determined using orthotopic injections. In Specific Aim 2 using transfections and co-immunoprecipitation approaches we will investigate the functional involvement of the Smad intracellular effectors of TGF-beta in transducing the apoptotic signals to the nucleus. In Specific Aim 3 the interaction between the androgen receptor (AR) and TGF-beta signaling pathways in LNCaP TbetaRII prostate cells will be characterized using immunoprecipitation assays. These studies will establish: a) that androgens contribute to the impairment of TGF-beta signaling in prostate cancer cells; and b) the significance of defects in post-receptor intracellular mediators of TGF-beta signal, the Smads, in the development of hormone-resistance in prostate cancer.