Pharmacological Targeting of Constitutively Active Truncated Androgen Receptor by Nigericin and Suppression of Hormone-Refractory Prostate Cancer Cell Growth
Pharmacological Targeting of Constitutively Active Truncated Androgen Receptor by Nigericin and Suppression of Hormone-Refractory Prostate Cancer Cell Growth
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DOI：
10.1124/mol.110.064790
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发表时间：
2010-11-01
影响因子：
3.6
通讯作者：
Seimiya, Hiroyuki
中科院分区：
文献类型：
--
作者：
Mashima, Tetsuo;Okabe, Sachiko;Seimiya, Hiroyuki
在前列腺癌中，阻断雄激素受体(AR)信号可以带来治疗上的好处。然而，这种标准疗法允许激素抵抗型前列腺癌(HRPC)复发，预后不佳。HRPC细胞经常表达变异的AR，如点突变等位基因和剪接异构体，导致雄激素非依赖性细胞生长和对抗雄激素(如氟他胺)的耐药性。然而，阻止这种异常ARs的药理策略仍有待建立。在这里，我们建立了一个报告系统，监测AR介导的前列腺特异性抗原(PSA)启动子的激活。我们的化学文库筛选显示，抗生素黑色素能抑制前列腺癌细胞中AR介导的PSA启动子的激活和PSA的产生。Nigericin抑制雄激素依赖的LNCaP细胞的生长，即使该细胞表达耐氟他胺突变AR。这些效应是由AR在mRNA和翻译后水平上的抑制引起的。在HRPC 22Rv1细胞中，表达全长AR和缺乏羧基末端配体结合域的活性截短ARs的HRPC 22Rv1细胞中，小干扰RNA介导的两种AR亚型的敲除都有效地抑制了雄激素非依赖性细胞的生长，而单独敲除全长AR没有明显的作用。值得注意的是，Nigericin能够模拟两种AR亚型的下调：它减少了全长和截短ARs的表达，并诱导了22Rv1细胞的G1期停滞和凋亡。这些观察结果表明，在mRNA水平抑制AR表达的黑素类化合物可能被用作新型治疗药物，抑制HRPC中广泛的AR变体。
In prostate cancer, blockade of androgen receptor (AR) signaling confers a therapeutic benefit. Nevertheless, this standard therapy allows relapse of hormone-refractory prostate cancer (HRPC) with a poor prognosis. HRPC cells often express variant ARs, such as point-mutated alleles and splicing isoforms, resulting in androgen-independent cell growth and resistance to antiandrogen (e. g., flutamide). However, a pharmacological strategy to block such aberrant ARs remains to be established. Here, we established a reporter system that monitors AR-mediated activation of a prostate-specific antigen (PSA) promoter. Our chemical library screening revealed that the antibiotic nigericin inhibits AR-mediated activation of the PSA promoter and PSA production in prostate cancer cells. Nigericin suppressed the androgen-dependent LNCaP cell growth even though the cells expressed a flutamide-resistant mutant AR. These effects were caused by AR suppression at the mRNA and post-translational levels. In HRPC 22Rv1 cells, which express the full-length AR and the constitutively active, truncated ARs lacking the carboxyl-terminal ligand-binding domain, small interfering RNA-mediated knockdown of both AR isoforms efficiently suppressed the androgen-independent cell growth, whereas knockdown of the full-length AR alone had no significant effect. It is noteworthy that nigericin was able to mimic the knockdown of both AR isoforms: it reduced the expression of the full-length and the truncated ARs, and it induced G 1 cell-cycle arrest and apoptosis of 22Rv1 cells. These observations suggest that nigericin-like compounds that suppress AR expression at the mRNA level could be applied as new-type therapeutic agents that inhibit a broad spectrum of AR variants in HRPC.