Coregulators in Androgen-Refractory Prostate Cancer

描述(申请人提供)：雄激素消融治疗是转移性前列腺癌(PCa)的一线治疗方法。尽管进行了这种治疗，前列腺癌最终仍将进展到雄激素抵抗阶段。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，也可以被非雄激素因素激活，如细胞因子白介素6(IL-6)。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AR的这种异位转录激活中起着重要的作用。我们已经证明，在IL-6刺激PCa细胞后，MAPK通路的组成部分被磷酸化，从而导致AR转录激活。我们已经证明，辅助激活因子p300介导了这种依赖IL-6的AR转录激活。我们的初步数据还表明，雄激素通过AR正向调节AR的表达。辅活化子FHL2，同时负性调节核受体辅阻遏子RIP140的表达。此外，在晚期前列腺癌的细胞模型中，我们观察到FHL2表达增加，RIP140表达减少。我们的数据还表明，FHL2与p300一起在转录上激活AR以响应IL-6。因此，我们推测p300、FHL2和RIP140在雄激素难治性前列腺癌进展过程中的AR转录激活中起重要作用。我们认为，在雄激素依赖的前列腺癌中，RIP140与AR形成复合体，从而限制AR对雄激素的激活。然而，一旦雄激素刺激，或当PCA进展到雄激素不耐受阶段时，这种复合体就会丢失。这种去抑制作用将允许非雄激素因子，如IL-6，诱导AR、p300和FHL2之间的复杂形成。为了验证这一假说，我们建议(1)确定通过MAPK途径调节的p300/FHL2复合体在IL-6介导的AR调节中的作用；(2)确定RIP140在IL-6介导的AR调节中的作用；(3)确定AR介导的FHL2诱导和RIP140抑制在雄激素依赖和难治性前列腺癌中的作用。这些研究将加深我们对雄激素难治性前列腺癌机制的理解，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.