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首页> 外文期刊>Cell cycle >Inhibition of Plk1 represses androgen signaling pathway in castration-resistant prostate cancer
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Inhibition of Plk1 represses androgen signaling pathway in castration-resistant prostate cancer

机译：Plk1抑制抑制去势抵抗性前列腺癌中的雄激素信号通路

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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.
机译：前列腺癌（PCa）是美国男性与癌症相关的死亡的第二大主要原因。大多数前列腺癌最初是雄激素依赖性的，并且对雄激素剥夺疗法（ADT）敏感，但是，大多数最终会复发并发展为无法治愈的去势抵抗性前列腺癌（CRPC）。值得注意的是，在CRPC阶段仍需要雄激素受体（AR）的活性。有丝分裂激酶polo样激酶1（Plk1）在PCa中显着升高，其表达与肿瘤等级相关。在这项研究中，我们评估Plk1对雄激素依赖性和非雄激素依赖性PCa细胞中AR信号的影响。我们证明Plk1的表达水平与致瘤性相关，并且抑制Plk1导致AR表达和AR活性降低。此外，Plk1抑制剂BI2536下调了雄激素生物合成相关酶的SREBP依赖性表达。有趣的是，当拮抗剂MDV3100抑制AR活性时，Plk1水平也会降低。最后，我们显示BI2536治疗可显着抑制LNCaP CRPC异种移植物中的肿瘤生长。总体而言，我们的数据支持Plk1抑制剂（例如BI2536）可阻止AR信号通路，并对CRPC患者具有治疗潜力的概念。

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