TGF-Beta Signaling Pathways in Prostate Tumorigenesis

描述（由申请人提供）：转化生长因子-b（TGF-β）是 前列腺生长的负调节剂，通过其抑制细胞增殖的能力， 增殖并诱导上皮细胞凋亡。证据表明 在前列腺癌中， 通过其膜受体TbetaRI和TbetaRII的表达丧失。的 拟议研究的长期目标是确定 前列腺肿瘤发生过程中的雄激素轴和TGF-β信号通路。 我们最近的研究表明， 人前列腺癌细胞LNCaP中的功能性TbetaRII受体， 抗TGF-β，导致TGF-β敏感性和抑制 通过细胞周期停滞和凋亡诱导的致瘤性生长。在这 建议我们将使用这种模型的细胞敏感的TGF-β反应， 前列腺癌细胞，以探索潜在的分子机制， 前列腺肿瘤发生中TGF-β信号通路功能障碍。在特定 目的1：我们将确定雄激素影响 TGF-β对前列腺癌细胞生长的影响与细胞周期失调有关 (cdk抑制剂）和凋亡诱导（半胱天冬酶，bcl-2）。的影响 雄激素对TGF-β介导的抑制体内肿瘤生长的作用 将使用原位注射测定LNCaP TbetaRII细胞。在 特异性目的2使用转染和免疫共沉淀方法， 将研究Smad细胞内效应物的功能参与 TGF-β在将凋亡信号转导至细胞核中的作用。在特定 目的3雄激素受体（AR）与TGF-β信号通路的相互作用 LNCaP TbetaRII前列腺细胞中的通路将使用 免疫沉淀测定。这些研究将确定：a）雄激素 有助于前列腺癌细胞中TGF-β信号传导的损伤; 和B）受体后细胞内介质缺陷的意义， TGF-β信号，Smads，在发展中国家的抗肿瘤， 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.