Inhibition of cholesterol biosynthesis overcomes enzalutamide resistance in castration-resistant prostate cancer (CRPC) X

Yifan Kong, Lijun Cheng, Fengyi Mao, Zhuangzhuang Zhang, Yanquan Zhang, Elia Farah, Jacob Bosler, Yunfeng Bai, Nihal Ahmad, Shihuan Kuang, Lang Li, Xiaoqi Liu

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Enzalutamide,a nonsteroidal second-generation antiandrogen, has been recently approved for the management of castration- resistant prostate cancer (CRPC).Although patients can benefit from enzalutamide at the beginning of this therapy, acquired enzalutamide resistance usually occurs within a short period.This motivated us to investigate the mechanism involved and possible approaches for overcoming enzalutamide resistance in CRPC. In the present study, we found that 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), a crucial enzyme in the mevalonate pathway for sterol biosynthesis, is elevated in enzalutamide-resistant prostate cancer cell lines. HMGCR knockdown could resensitize these cells to the drug, andHMGCRoverexpression conferred resistance to it, suggesting that aberrant HMGCR expression is an important enzalutamide- resistance mechanism in prostate cancer cells.Furthermore, enzalutamide-resistant prostate cancer cells were more sensitive to statins,which are HMGCR inhibitors.Of note,a combination of simvastatin and enzalutamide significantly inhibited the growth of enzalutamide-resistant prostate cancer cells in vitro and tumors in vivo. Mechanistically,simvastatin decreased protein levels of the androgen receptor (AR),which was further reduced in combination with enzalutamide.We observed that the decrease in AR may occur through simvastatin- mediated inhibition of themTORpathway, whose activation was associated with increased HMGCR and AR expression.These results indicate that simvastatin enhances the efficacy of enzalutamide-based therapy, highlighting the therapeutic potential of statins to overcome enzalutamide resistance in CRPC.

Original languageEnglish
Pages (from-to)14328-14341
Number of pages14
JournalJournal of Biological Chemistry
Volume293
Issue number37
DOIs
StatePublished - Sep 14 2018

Bibliographical note

Publisher Copyright:
©2018The American Society for Biochemistry and Molecular Biology, Inc.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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