Molecular Regulation of Androgen Receptor Activation

描述：(申请人提供)当前的总体目标 建议的目的是为了了解 晚期前列腺癌激素不敏感机制的初步探讨 AR的激活过程。激素非依赖性前列腺癌的出现 会降低荷尔蒙疗法的有效性。前列腺癌的一种发病机制 肿瘤细胞绕过激素治疗是引入/选择突变株 雄激素受体(AR)，最终将拮抗剂转变为激动剂。 在体内和体外都很明显。其他的扰动正在导致 激素非依赖性AR激活。例如，脚手架--洞穴的等级 与小窝信号微域相关的蛋白质，已经被关联 与前列腺癌的激素抵抗和转移有关。我们在以下方面进行演示 小窝蛋白水平的调节显著改变了细胞模型 AR对雄激素的敏感性。此外，瞬变和动态的直接关系 AR和小窝蛋白在雄激素刺激下的相互作用也是 演示了。我们的工作假设是AR的激活可能是 由串扰调节，与信号复合体相关联 含有小窝的小窝。目前的提案旨在严格地 从分子、细胞和分子水平评价AR与小窝蛋白-1的相互作用 生理水平。近期目标是：(1)详细界定 AR与小窝蛋白-1在分子水平上的相互作用；(2)在功能上 雄激素受体中AR与小窝蛋白-1相互作用的研究 激活；(3)表征小窝蛋白的生理作用 前列腺癌细胞培养模型中AR信号的过度表达； (4)研究小窝蛋白-1过表达对LNCaP细胞的影响 裸鼠移植瘤模型的致瘤性和转移性。完全 AR和洞穴之间的相互作用的特征可以外推到 前列腺癌进展的病理生物学认识及临床意义 AR信号的正常前列腺上皮生理学。长期目标 是确定新的目标和机制，这在未来可能是有用的 开发合理的药物靶点。

DESCRIPTION: (provided by the applicant) The overall objectives of the current proposal are directed at understanding the molecular mechanism underlying the hormone insensitivity in advanced prostate cancer by delineating the mechanism of AR activation process. The emergence of hormone-independent prostate cancer curtails the effectiveness of hormonal therapies. One mechanism for prostate cancer cells to circumvent the hormonal therapy is to introduce/select mutant androgen receptors (AR), which eventually turn an antagonist into an agonist as evident both in vivo and in vitro. Other perturbations are leading to hormone-independent AR activation. For example, levels of caveolin, a scaffold protein associated with caveolae signaling microdomains, have been correlated with hormone resistance and metastasis in prostate cancer. We demonstrate in cellular models that modulations in caveolin levels dramatically alter the sensitivity of AR to androgen. Furthermore, a transient and dynamic direct interaction between AR and caveolin in response to androgen stimulation is also demonstrated. Our working hypothesis is that AR activation is potentially regulated by a crosstalk with signal complexes associated with caveolin-containing caveolae. The current proposal is designed to rigorously evaluate the interaction between AR and caveolin-1 at molecular, cellular and physiological levels. The immediate goals are: (1) to define in detail the interaction between AR and caveolin-1 at molecular level; (2) to functionally characterize the interaction between AR and caveolin-1 in androgenic receptor activation; (3) to characterize the physiological role of caveolin overexpression in AR signaling using a prostate carcinoma cell culture model; (4) to characterize the effect of caveolin-1 overexpression on LNCap cell tumorigenicity and metastasis using a nude mouse xenograft model. Fully characterizing the interaction between AR and caveolin can be extrapolated to the understanding of the pathobiology of prostate cancer progression as well as the normal prostate epithelial physiology of AR signaling. The long-term goals are to identify novel targets and mechanisms, which could be useful in future development of rational drug targets.