Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer.
Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer.
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DOI：
10.1158/1535-7163.mct-16-0241
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发表时间：
2016-09
影响因子：
5.7
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Chen L;Li J;Farah E;Sarkar S;Ahmad N;Gupta S;Larner J;Liu X
去势抵抗性前列腺癌（CRPC）是前列腺癌（PCa）的晚期，当疾病对雄激素剥夺治疗（ADT）停止反应时。已经确定雄激素受体（AR）再激活是ADT后PCa复发的原因。因此，靶向调节AR稳定性和活性的不同途径应该是治疗CRPC的一个有希望的策略。热休克蛋白（HSPs）是改变其客户蛋白的稳定性和活性的伴侣蛋白。HSP90是HSP家族的主要成员，调节许多蛋白质的稳定性，包括AR和polo样激酶1 (Plk1)，这是许多细胞周期事件的关键调节因子。此外，HSP90在不同的癌症中过表达，包括前列腺癌。本研究表明，由于AR蛋白的协同减少，PCa与AR拮抗剂恩杂鲁胺和HSP90抑制剂共同处理会导致更严重的细胞死亡。有趣的是，我们发现Plk1的过表达挽救了协同效应，而共同靶向HSP90和Plk1也会导致更严重的细胞死亡。从机制上讲，我们发现E3连接酶CHIP除了靶向AR外，还负责Plk1的降解。这些发现表明，共同靶向HSP90及其一些客户蛋白可能是治疗CRPC的有效策略。
Castration-resistant prostate cancer (CRPC) is the later stage of prostate cancer (PCa) when the disease has stopped responding to androgen deprivation therapy (ADT). It has been established that androgen receptor (AR) re-activation is responsible for the recurrence of PCa after ADT. Thus targeting different pathways that regulate AR stability and activity should be a promising strategy for treatment of CRPC. Heat shock proteins (HSPs) are chaperones that modify stability and activity of their client proteins. HSP90, a major player of the HSP family, regulates stabilities of many proteins, including AR and Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events. Further, HSP90 is overexpressed in different cancers, including PCa. Herein, we show that co-treatment of PCa with AR antagonist enzalutamide and HSP90 inhibitor leads to more severe cell death due to a synergistic reduction of AR protein. Interestingly, we show that overexpression of Plk1 rescued the synergistic effect and that co-targeting HSP90 and Plk1 also leads to more severe cell death. Mechanistically, we show that E3 ligase CHIP, in addition to targeting AR, is responsible for the degradation of Plk1 as well. These findings suggest that co-targeting HSP90 and some of its client proteins may be a useful strategy in treatment of CRPC.