Coregulators in Androgen-Refractory Prostate Cancer

描述（由申请人提供）：雄激素消融治疗是转移性前列腺癌（PCa）的一线治疗。尽管这种治疗，PCa最终将进展到雄激素难治期。虽然雄激素难治性前列腺癌没有有效的治疗方法，但雄激素受体（AR）在疾病的这个阶段继续发挥作用。事实上，在这个阶段，AR对低雄激素水平敏感，并且也可以被非雄激素因子如细胞因子白细胞介素-6（IL-6）激活。一些研究，包括我们自己的研究，表明AR共调节蛋白的去调节在这种混杂的AR转录激活中起着重要作用。我们已经表明，在IL-6刺激PCa细胞后，MAPK途径的组分被磷酸化，从而导致AR转录激活。我们已经证明，辅激活因子p300介导这种IL-6依赖性AR转录激活。我们的初步数据还表明，雄激素，通过AR，积极调节AR的表达。辅激活因子FHL 2，同时负调节核受体辅阻遏因子RIP 140的表达。此外，我们在晚期前列腺癌的细胞模型中观察到FHL 2表达增加和RIP 140表达减少。我们的数据还表明，FHL 2与p300在转录激活AR响应IL-6中起作用。因此，我们推测，在雄激素难治性前列腺癌进展过程中，辅助调节因子p300、FHL 2和RIP 140在AR转录激活中起重要作用。我们认为，在雄激素依赖性前列腺癌，RIP 140与AR形成复合物，从而限制了雄激素对AR的激活。然而，在雄激素刺激时，或当PCa进展到雄激素难治期时，这种复合物丢失。这种去阻遏然后将允许非雄激素因子如IL-6诱导AR、p300和FHL 2之间的复合物形成。为了验证这一假设，我们建议（1）确定通过MAPK途径调节的p300/FHL 2复合物在IL-6介导的AR调节中的作用;（2）确定RIP 140在IL-6介导的AR调节中的作用;（3）确定AR介导的FHL 2诱导和RIP 140抑制在雄激素依赖性和难治性PCa中的作用。这些研究应加强我们对雄激素难治性前列腺癌的机制的理解，并可能导致新的治疗靶点的确定。

DESCRIPTION (provided by applicant): Androgen ablation therapy is the first line treatment for metastatic prostate cancer (PCa). Despite this treatment, PCa will eventually progress to an androgen refractory stage. Although there is no effective therapy for androgen refractory PCa, the androgen receptor (AR) continues to play a role at this stage of the disease. Indeed, at this stage the AR is sensitized to low androgen levels, and can also be activated by non-androgenic factors such as the cytokine, interleukin-6 (IL-6). Several studies, including our own, indicate that de-regulation of AR coregulatory proteins plays an important role in this promiscuous transcriptional activation of the AR. We have shown that, following IL-6 stimulation of PCa cells, components of the MAPK pathway are phosphorylated, thus leading to AR transcriptional activation. We have shown that the coactivator p300 mediates this IL-6-dependent AR transcriptional activation. Our preliminary data also shows that androgens, through the AR, positively regulate expression of the AR. coactivator, FHL2, while negatively regulating expression of the nuclear receptor corepressor, RIP140. Furthermore, we have observed increased FHL2 expression and reduced RIP140 expression in cell-based models of advanced prostate cancer. Our data also suggest that FHL2 plays a role in conjunction with p300 in transcriptionally activating the AR in response to IL-6. We thus hypothesize that the coregulators p300, FHL2, and RIP140 play important roles in AR transcriptional activation during androgen refractory progression of PCa. We suggest that in androgen-dependent PCa, RIP140 forms a complex with the AR, thus limiting the activation of the AR to androgens. However, upon androgen stimulation, or when PCa progresses to an androgen refractory stage, this complex is lost. This de-repression would then allow non-androgenic factors such as IL-6 to induce complex formation between the AR, p300, and FHL2. To test this hypothesis, we propose to (1) determine the role of the p300/FHL2 complex modulated through the MAPK pathway in the IL-6 mediated regulation of the AR; (2) determine the role of RIP140 in the IL-6 mediated regulation of the AR; and (3) determine the role of AR-mediated FHL2 induction and RIP140 repression in androgen dependent and refractory PCa. These studies should enhance our understanding of the mechanisms involved in androgen refractory PCa, and may lead to the identification of new therapeutic targets.