Activity of androgen receptor antagonist bicalutamide in prostate cancer cells is independent of NCoR and SMRT corepressors
Activity of androgen receptor antagonist bicalutamide in prostate cancer cells is independent of NCoR and SMRT corepressors
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DOI：
10.1158/0008-5472.can-07-0617
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发表时间：
2007-09-01
期刊：
影响因子：
11.2
通讯作者：
Balk, Steven P.
中科院分区：
文献类型：
--
作者：
Hodgson, Myles C.;Astapova, Inna;Balk, Steven P.
雄激素受体(AR)拮抗剂抑制AR活性的机制，以及在雄激素剥夺治疗后进展的前列腺癌中，它们的拮抗剂活性如何被取消，目前尚不清楚。最近的研究表明，AR拮抗剂(包括临床使用的药物比卡鲁胺)可以增加辅阻遏物蛋白[核受体辅阻遏物(NCoR)和维甲酸和甲状腺受体沉默介体(SMRT)]的AR募集，辅阻遏物的丢失可能增强激动剂的活性，是拮抗剂失效的机制之一。我们首先证明了弱雄激素和AR拮抗剂(乙酸环丙孕酮)的激动剂活性仍然依赖于AR NH2/COOH-末端的相互作用，并被类固醇受体共激活剂(SRC)-1增强，而双卡路胺修饰的AR没有发生可检测到的NH2/COOH-末端相互作用，也不被SRC-1共激活。然而，分离的AR NH2末端和比卡鲁胺连接的AR都可以与SRG-1富含谷氨酰胺的结构域相互作用，该区域介导NH2末端的空气结合。为了确定比卡鲁胺激动剂活性是否受到NCoR募集的抑制，我们使用小干扰RNA来耗尽CV1细胞中的NCoR以及LNCaP前列腺癌细胞中的NCoR和SMRT。这些辅抑制子的缺失增强了双氢睾酮刺激的LNCaP细胞报告基因和内源性AR调节的PSA基因上的AR活性，但没有发现任何可检测到的比卡鲁胺激动剂活性。综上所述，这些结果表明，比卡鲁胺缺乏激动剂活性，而作为AR拮抗剂的作用是由于辅助激活蛋白的无效招募，而辅助激活蛋白招募的增强而不是辅阻遏物的丧失可能是比卡鲁胺耐药的机制之一。
The mechanisms by which androgen receptor (AR) antagonists inhibit AR activity, and how their antagonist activity may be abrogated in prostate cancer that progresses after androgen deprivation therapy, are not clear. Recent studies show that AR antagonists (including the clinically used drug bicalutamide) can enhance AR recruitment of corepressor proteins [nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid receptors (SMRT)] and that loss of corepressors may enhance agonist activity and be a mechanism of antagonist failure. We first show that the agonist activities of weak androgens and an AR antagonist (cyproterone acetate) are still dependent on the AR NH2/COOH-terminal interaction and are enhanced by steroid receptor coactivator (SRC)-1, whereas the bicalutamideliganded AR did not undergo a detectable NH2/COOH-terminal interaction and was not coactivated by SRC-1. However, both the isolated AR NH2 terminus and the bicalutamide-liganded AR could interact with the SRG-1 glutamine-rich domain that mediates AIR NH2-terminal binding. To determine whether bicalutamide agonist activity was being suppressed by NCoR recruitment, we used small interfering RNA to deplete NCoR in CV1 cells and both NCoR and SMRT in LNCaP prostate cancer cells. Depletion of these corepressors enhanced dihydrotestosterone-stimulated AR activity on a reporter gene and on the endogenous AR-regulated PSA gene in LNCaP cells but did not reveal any detectable bicalutamide agonist activity. Taken together, these results indicate that bicalutamide lacks agonist activity and functions as an AR antagonist due to ineffective recruitment of coactivator proteins and that enhanced coactivator recruitment, rather than loss of corepressors, may be a mechanism contributing to bicalutamide resistance.