Inhibition of Plk1 represses androgen signaling pathway in castration-resistant prostate cancer

Prostate cancer (PCa) is the second leading cause of cancer-related death in males in the United States. Majority of prostate cancers are originally androgen-dependent and sensitive to androgen-deprivation therapy (ADT), however, most of them eventually relapse and progress into incurable castration-resistant prostate cancer (CRPC). Of note, the activity of androgen receptor (AR) is still required in CRPC stage. The mitotic kinase polo-like kinase 1 (Plk1) is significantly elevated in PCa and its expression correlates with tumor grade. In this study, we assess the effects of Plk1 on AR signaling in both androgen-dependent and androgen-independent PCa cells. We demonstrate that the expression level of Plk1 correlated with tumorigenicity and that inhibition of Plk1 caused reduction of AR expression and AR activity. Furthermore, Plk1 inhibitor BI2536 down-regulated SREBP-dependent expression of enzymes involved in androgen biosynthesis. Of interest, Plk1 level was also reduced when AR activity was inhibited by the antagonist MDV3100. Finally, we show that BI2536 treatment significantly inhibited tumor growth in LNCaP CRPC xenografts. Overall, our data support the concept that Plk1 inhibitor such as BI2536 prevents AR signaling pathway and might have therapeutic potential for CRPC patients.     

雄激素受体共调节因子与雄激素非依赖性前列腺癌

雄激素介导的雄激素受体（AR）信号途径对雄性胚胎的发育及雄激素依赖性靶组织的分化发育是必需的。异常的AR活性与前列腺癌由雄激素依赖转变为雄激素非依赖性密切相关。已证实AR共调节因子参与前列腺癌的发生和发展,并在雄激素非依赖性前列腺癌细胞的增殖中扮演着重要角色。它们的表达失衡,可导致AR转录活性的改变,促进晚期前列腺癌的进展。简要综述了AR共调节因子的类型和功能,及其与雄激素非依赖性前列腺癌的关系。     

雄激素受体共调节因子及其在前列腺癌进展中的作用

雄激素受体（AR）信号通路在前列腺癌的发生、进展和转移中发挥着重要作用,但AR介导组织对雄激素的特异应答是通过与其相互作用的AR共调节因子共同完成的,许多AR共调节因子的功能已被广泛研究。简要综述了目前发现的部分AR共调节因子在调节AR转录活性及前列腺癌发生、进展中的生物学作用。     

雄激素受体信号转导途径及其在前列腺癌发展中的作用

前列腺癌是西方男性发病率最高的癌症之一,在采用雄激素阻断疗法后,大部分患者的病情可得到控制,但经过一段时间又会转变为雄激素非依赖型前列腺癌。雄激素受体(AR)在前列腺细胞中扮演重要的角色,它可调节大量基因的表达。在前列腺癌由雄激素依赖型向雄激素非依赖型的转变过程中,AR及其信号途径通过多种方式发挥作用,AR基因的扩增、AR的突变,以及与共激活子之间作用的改变都可能使细胞获得雄激素非依赖型的生长能力。此外,AR还受到多肽生长因子和细胞因子等的调节,表现激素非依赖型的转录激活活性。AR在前列腺癌中作用的阐明对前列腺癌的诊断与治疗有着重大的意义。     

阻断MAPK通路促进雄激素受体招募NCoR并抑制前列腺癌细胞生长

雄激素受体（androgen receptor, AR）是配体调节的转录因子,与前列腺癌的生长和内分泌治疗密切相关。 醋酸环丙孕酮（cyproterone acetate, CPA）作为雄激素的拮抗剂已用于前列腺癌的治疗。结合了CPA的AR可与核受体协同抑制因子作用。已证实丝裂原激活的蛋白激酶（mitogen-activated protein kinase, MAPK）可介导生长因子和雄激素受体的信号转导通路的交互作用。我们报道,激活的MAPK抑制结合了CPA的AR招募核受体协同抑制因子(nuclear receptor corepressor, NCoR)至雄激素反应元件上。应用MEK的抑制剂U0126阻断MAPK通路可促进结合了CPA的AR和NCoR相互作用并通过对NCoR的招募增加抑制AR的功能从而阻遏AR靶基因的表达。此外,联合使用CPA和U0126处理稳定表达NCoR的LNCaP细胞可显著抑制前列腺癌细胞的生长。本研究表明,联合应用AR的拮抗剂和MAPK抑制剂有助于前列腺癌的治疗。