雄激素受体
前列腺癌
醋酸阿比特龙酯
癌症研究
雄激素
CYP17A1型
核受体
交易激励
癌症
内科学
雄激素剥夺疗法
生物
医学
内分泌学
转录因子
基因
激素
生物化学
作者
Lijia Xiao,Yuliang Wang,Kexin Xu,Hao Hu,Zhenyu Xu,Dinglan Wu,Zhu Wang,Wenxing You,Chi‐Fai Ng,Shan Yu,Franky Leung Chan
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2018-02-13
卷期号:78 (9): 2205-2218
被引量:41
标识
DOI:10.1158/0008-5472.can-17-2341
摘要
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 anti-androgen 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. Cancer Res; 78(9); 2205-18. ©2018 AACR.
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