Rapamycin inhibits AR signaling pathway in prostate cancer by interacting with the FK1 domain of FKBP51
Rapamycin inhibits AR signaling pathway in prostate cancer by interacting with the FK1 domain of FKBP51
复制标题
雷帕霉素通过与 FKBP51 的 FK1 结构域相互作用抑制前列腺癌中的 AR 信号通路
DOI：
10.1016/j.bbrep.2020.100778
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发表时间：
2020-09-01
影响因子：
2.7
通讯作者：
Wang, Zhiping
中科院分区：
文献类型：
--
作者：
Zhang, Jing;Wu, Dan;Wang, Zhiping
雄激素受体信号通路在去势环境中的重新激活是去势抵抗前列腺癌(CRPC)发生的主要原因。免疫亲和素FKBP51作为辅助伴侣蛋白，与Hsp90一起帮助AR正确折叠。雷帕霉素是一种已知的FKBP51小分子抑制剂，但其对FKBP51/AR信号通路的作用尚不清楚。本研究采用稳态荧光猝灭、X射线结晶分析、四甲基偶氮唑盐比色法、定量逆转录聚合酶链式反应等方法研究了FKBP51与雷帕霉素的相互作用机理。稳态荧光猝灭实验表明雷帕霉素能与FKBP51相互作用。雷帕霉素-FKBP51复合物的结晶表明，雷帕霉素占据了对AR活性至关重要的FK1结构域的疏水结合口袋。与雷帕霉素结合的残基主要是疏水性的，可能与AR相互作用部位重叠。进一步的分析表明，雷帕霉素可以通过下调AR激活的下游基因的表达水平来抑制人前列腺癌细胞的雄激素依赖性生长。综上所述，我们的研究表明，雷帕霉素通过干扰AR和FKBP51之间的相互作用来抑制AR信号通路。本研究结果不仅可以为雷帕霉素与FKBP51相互作用机制提供有用的信息，也可以为前列腺癌和去势耐受前列腺癌的治疗提供新的线索。
Reactivation of the androgen receptor signaling pathway in the emasculated environment is the main reason for the occurrence of castration-resistant prostate cancer (CRPC). The immunophilin FKBP51, as a co-chaperone protein, together with Hsp90 help the correct folding of AR. Rapamycin is a known small-molecule inhibitor of FKBP51, but its effect on the FKBP51/AR signaling pathway is not clear. In this study, the interaction mechanism between FKBP51 and rapamycin was investigated using steady-state fluorescence quenching, X-ray crystallization, MTT assay, and qRT-PCR. Steady-state fluorescence quenching assay showed that rapamycin could interact with FKBP51. The crystal of the rapamycin-FKBP51 complex indicated that rapamycin occupies the hydrophobic binding pocket of FK1 domain which is vital for AR activity. The residues involving rapamycin binding are mainly hydrophobic and may overlap with the AR interaction site. Further assays showed that rapamycin could inhibit the androgen-dependent growth of human prostate cancer cells by down-regulating the expression levels of AR activated downstream genes. Taken together, our study demonstrates that rapamycin suppresses AR signaling pathway by interfering with the interaction between AR and FKBP51. The results of this study not only can provide useful information about the interaction mechanism between rapamycin and FKBP51, but also can provide new clues for the treatment of prostate cancer and castration-resistant prostate cancer.