Nuclear receptor ERRα contributes to castration-resistant growth of prostate cancer via its regulation of intratumoral androgen biosynthesis
Nuclear receptor ERRα contributes to castration-resistant growth of prostate cancer via its regulation of intratumoral androgen biosynthesis
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核受体 ERRα 通过调节瘤内雄激素生物合成促进前列腺癌的去势抵抗性生长
DOI：
10.7150/thno.35589
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Chan, Franky Leung
中科院分区：
文献类型：
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作者：
Xu, Zhenyu;Ma, Taiyang;Chan, Franky Leung
增强的瘤内雄激素生物合成和持续的雄激素受体（AR）信号传导是导致去势抵抗性前列腺癌（CRPC）复发的关键因素。残留的前列腺内雄激素可以通过胆固醇从头合成雄激素或通过前列腺癌细胞中表达的类固醇生成酶通过不同的类固醇生成途径从肾上腺雄激素转化而产生。然而，CRPC中雄激素生物合成酶的失调仍然知之甚少。本研究旨在阐明雌激素相关受体α（ERRα，ESRRA）在CRPC生长过程中促进雄激素生物合成的作用。方法：采用基因表达Omnibus（GEO）数据集分析CRPC患者ERRα的表达，并在已建立的CRPC异种移植模型中进行验证。通过过表达和敲低研究阐明了ERRα在促进去势抵抗性生长中的作用，并通过UPLC-MS/MS测量了瘤内雄激素水平。使用ERRα反向激动剂确定了ERRα活性抑制对雄激素剥夺敏感性增强的影响。ERRα在转移性CRPC和CRPC异种移植模型中表现出表达增加，可通过直接反式激活两种关键雄激素合成酶CYP 11 A1和AKR 1C 3来促进去势抗性生长，并因此增强前列腺内双氢睾酮（DHT）的产生和前列腺癌细胞中AR信号传导的激活。值得注意的是，通过反向激动剂XCT 790抑制ERRα活性可以减少前列腺癌细胞中DHT的产生并抑制AR信号转导。结论：我们的研究揭示了ERRα通过其类固醇生成酶的转录控制在CRPC肿瘤内雄激素生物合成中的新作用，并且还提供了一种新的见解，靶向ERRα可能是一种潜在的雄激素剥夺策略用于CRPC的管理。
Enhanced intratumoral androgen biosynthesis and persistent androgen receptor (AR) signaling are key factors responsible for the relapse growth of castration-resistant prostate cancer (CRPC). Residual intraprostatic androgens can be produced by de novo synthesis of androgens from cholesterol or conversion from adrenal androgens by steroidogenic enzymes expressed in prostate cancer cells via different steroidogenic pathways. However, the dysregulation of androgen biosynthetic enzymes in CRPC still remains poorly understood. This study aims to elucidate the role of the nuclear receptor, estrogen-related receptor alpha (ERRα, ESRRA), in the promotion of androgen biosynthesis in CRPC growth.Methods: ERRα expression in CRPC patients was analyzed using Gene Expression Omnibus (GEO) datasets and validated in established CRPC xenograft model. The roles of ERRα in the promotion of castration-resistant growth were elucidated by overexpression and knockdown studies and the intratumoral androgen levels were measured by UPLC-MS/MS. The effect of suppression of ERRα activity in the potentiation of sensitivity to androgen-deprivation was determined using an ERRα inverse agonist.Results: ERRα exhibited an increased expression in metastatic CRPC and CRPC xenograft model, could act to promote castration-resistant growth via direct transactivation of two key androgen synthesis enzymes CYP11A1 and AKR1C3, and hence enhance intraprostatic production of dihydrotestosterone (DHT) and activation of AR signaling in prostate cancer cells. Notably, inhibition of ERRα activity by an inverse agonist XCT790 could reduce the DHT production and suppress AR signaling in prostate cancer cells.Conclusion: Our study reveals a new role of ERRα in the intratumoral androgen biosynthesis in CRPC via its transcriptional control of steroidogenic enzymes, and also provides a novel insight that targeting ERRα could be a potential androgen-deprivation strategy for the management of CRPC.