Nuclear Receptor LRH-1 Functions to Promote Castration-Resistant Growth of Prostate Cancer via Its Promotion of Intratumoral Androgen Biosynthesis
Nuclear Receptor LRH-1 Functions to Promote Castration-Resistant Growth of Prostate Cancer via Its Promotion of Intratumoral Androgen Biosynthesis
复制标题
核受体LRH-1通过促进瘤内雄激素生物合成来促进前列腺癌的去势抗性生长
DOI：
10.1158/0008-5472.can-17-2341
复制
发表时间：
2018-05-01
期刊：
影响因子：
11.2
通讯作者：
Chan, Franky Leung
中科院分区：
文献类型：
--
作者：
Xiao, Lijia;Wang, Yuliang;Chan, Franky Leung
靶向甾体原酶（如靶向CYP17A1的醋酸阿比特龙）已成为一种治疗转移性去势抵抗性前列腺癌（CRPC）的新策略。然而，患者不可避免地会产生对类固醇抑制剂的耐药性，其机制在很大程度上仍然未知。肝脏受体同源物-1 （Liver receptor homology -1, LRH-1, NR5A2）是一种核受体，最初被认为是一些肝脏特异性代谢基因的重要调节因子。在这里，我们报道了LRH-1在高级别前列腺癌和CRPC异种移植模型中表现出增加的表达模式，通过直接激活几个关键的类固醇酶基因，在CRPC异种移植和阿比特龙治疗的CRPC肿瘤中提高肿瘤内雄激素水平和重新激活AR信号，促进新生雄激素的生物合成。LRH-1活性的药理学抑制可减弱LRH-1介导的雄激素剥夺和前列腺癌细胞的抗雄激素抗性。我们的研究结果不仅证明了LRH-1通过直接转录控制激素生成在CRPC中促进肿瘤内雄激素生物合成的重要作用，而且表明靶向LRH-1可能是治疗CRPC的潜在治疗策略。意义：这些发现不仅证明了核受体LRH-1通过直接转录控制甾体生成在促进CRPC肿瘤内雄激素生物合成中的重要作用，而且表明靶向LRH-1可能是治疗CRPC的潜在治疗策略。(c) 2018年aacr。
Targeting of steroidogenic enzymes (e.g., abiraterone acetate targeting CYP17A1) has been developed as a novel therapeutic strategy against metastatic castration-resistant prostate cancer (CRPC). However, resistance to steroidal inhibitors inevitably develops in patients, the mechanisms of which remain largely unknown. Liver receptor homolog-1 (LRH-1, NR5A2) is a nuclear receptor, originally characterized as an important regulator of some liver-specific metabolic genes. Here, we report that LRH-1, which exhibited an increased expression pattern in high-grade prostate cancer and CRPC xenograft models, functions to promote de novo androgen biosynthesis via its direct transactivation of several key steroidogenic enzyme genes, elevating intratumoral androgen levels and reactivating AR signaling in CRPC xenografts as well as abiraterone-treated CRPC tumors. Pharmacologic inhibition of LRH-1 activity attenuated LRH-1-mediated androgen deprivation and antiandrogen resistance of prostate cancer cells. Our findings not only demonstrate the significant role of LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management.Significance: These findings not only demonstrate the significant role of the nuclear receptor LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management. (C) 2018 AACR.