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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.
Androgen receptor (AR), a ligand-regulated transcription factor, is closely related to the growth and endocrine therapy of prostate cancer. Cyproterone acetate (CPA) has been used as an androgen antagonist in prostate Cancer treatment AR combined with CPA acts as a synergistic inhibitor of nuclear receptors Mitogen-activated protein kinase (MAPK) has been shown to mediate signal transduction of growth factors and androgen receptors We report that activated MAPK inhibits the recruitment of nuclear receptor corepressor (NCoR) to the androgen response element by AR that binds to CPA.Using inhibitor U0126 of MEK to block the MAPK pathway can promote AR combined with NCoR of CPA and repressed the expression of AR target by inhibiting the function of AR by recruiting NCoR.In addition, LNCaP cells stably expressing NCoR combined with CPA and U0126 significantly inhibited the growth of prostate cancer cells This study shows that the combination of AR antagonists and MAPK inhibitors contributes to the treatment of prostate cancer.