Coactivators in Androgen-Refractory Prostate Cancer

描述（由申请人提供） 激素治疗是晚期前列腺癌最常见的治疗方法。 然而，患者通常死于雄激素抵抗型疾病 没有进一步治疗的希望我们的实验室已经证明， 雄激素受体（AR）的破坏抑制了 雄激素难治性前列腺癌细胞。此外，AR可以被非雄激素激活。 因子，如IL-6和IGF-I。这就突出了研究 雄激素难治性前列腺癌中AR激活的分子机制 PCa。因此，我们将注意力集中在协同调节因子在 AR的雄激素非依赖性激活。研究表明 辅助激活因子CBP和p300是IL-6介导的转录激活所必需的。 AR. CBP似乎通过结合AR发挥作用; p300似乎通过结合 STAT 3是IL-6通路的一个组成部分。此外，两个核心组件 人SWI/SNF复合物BAF 170和BAF 60 b在小鼠中过表达， 雄激素难治性前列腺癌细胞。根据这些数据，我们假设IL-6诱导的 AR的反式激活由AR-STAT 3相互作用bar募集介导 转录辅助调节因子的作用。包括CBP、p300和 SWI/SNF复合体。为了检验这一假设，我们建议（1）确定 CBP/AR复合物为IL-6诱导的IL-10反式激活提供了基础。 （2）确定p300/STAT 3复合物募集到AR中是否是AR的关键 IL-6诱导的AR反式激活中的因子;（3）确定核心是否 SWI/SNF复合物的组分促进IL-6诱导的 的AR。这些研究应该加强我们对雄激素难治性 前列腺癌，并可能为这种疾病确定新的治疗靶点。

DESCRIPTION (Provided by the applicant) Hormonal therapy is the most common treatment for advanced prostate cancer. However, patients usually die of an androgen-refractory form of the disease with no hope for further treatment. Our laboratory has demonstrated that disruption of the androgen receptor (AR) inhibits proliferation of androgen-refractory PCa cells. Moreover, AR can be activated by nonandrogenic factors, such as IL-6 and IGF-I. This has accentuated the need to study the molecular mechanisms underlying the activation of the AR in androgen-refractory PCa. Thus, we have focused our attention on the role of coregulators in androgen-independent activation of the AR. Studies suggest that the coactivators CBP and p300 are required for IL-6-mediated transactivation of the AR. CBP appears to act by binding to the AR; p300 appears to act by binding to STAT3, a component of the IL-6 pathway. Additionally, two core components of the human SWI/SNF complex, BAF170 and BAF60b, are overexpressed in androgen-refractory PCa cells. From these data we hypothesize that IL-6-induced transactivation of AR is mediated by the AR-STAT3 interaction bar recruitment of transcriptional coregulators. including CBP, p300 and components of the SWI/SNF complex. To test this hypothesis, we propose to (1) determine if the CBP/AR complex provides a foundation for IL-6-induced transactivation of the AR; (2) determine if the recruitment of the p300/STAT3 complex into AR is a key factor in IL-6-induced transactivation of the AR; (3) determine if the core components of the SWI/SNF complex facilitate IL-6-induced transactivation of the AR. These studies should enhance our understanding of androgen-refractory prostate cancer and may identify new therapeutic targets for this disease.