期刊
THERANOSTICS
卷 7, 期 7, 页码 1914-1927出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.17852
关键词
Triptolide; Enzalutamide; Castration-resistant prostate cancer; Androgen receptor; Phosphorylation
资金
- National Natural Science Foundation of China [31571194, 81672873, 81372168]
- National Forestry Public Welfare Industry Research Project [201204603]
- Research Innovation Team Project of Shaanxi [2013KCT-27]
- Natural Science Foundation for Universities in Jiangsu Province [BK20151396]
- National Key Research and Development Plan of China [2016YFC0902202]
- One Hundred Talent Program of Chinese Academy of Sciences
- Research Fund of Institutes for Drug Discovery and Development, Chinese Academy of Sciences [CASIMM0120164001]
Enzalutamide is a second-generation androgen receptor (AR) antagonist for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Unfortunately, AR dysfunction means that resistance to enzalutamide will eventually develop. Thus, novel agents are urgently needed to treat this devastating disease. Triptolide (TPL), a key active compound extracted from the Chinese herb Thunder God Vine (Tripterygium wilfordii Hook F.), possesses anti-cancer activity in human prostate cancer cells. However, the effects of TPL against CRPC cells and the underlying mechanism of any such effect are unknown. In this study, we found that TPL at low dose inhibits the transactivation activity of both full-length and truncated AR without changing their protein levels. Interestingly, TPL inhibits phosphorylation of AR and its CRPC-associated variant AR-V7 at Ser515 through XPB/CDK7. As a result, TPL suppresses the binding of AR to promoter regions in AR target genes along with reduced TFIIH and RNA Pol II recruitment. Moreover, TPL at low dose reduces the viability of prostate cancer cells expressing AR or AR-Vs. Low-dose TPL also shows a synergistic effect with enzalutamide to inhibit CRPC cell survival in vitro, and enhances the anti-cancer effect of enzalutamide on CRPC xenografts with minimal side effects. Taken together, our data demonstrate that TPL targets the transactivation activity of both full-length and truncated ARs. Our results also suggest that TPL is a potential drug for CRPC, and can be used in combination with enzalutamide to treat CRPC.
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