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.
|Number of pages||14|
|Journal||Journal of Biological Chemistry|
|State||Published - Sep 14 2018|
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health Grants R01 CA157429 (to X. L.), R01 CA192894 (to X. L.), R01 CA196835 (to X. L.), R01 CA196634 (to X. L.), R01 AR059130 (to N. A.), and R01 CA176748 (to N. A.) and by funds from the Chinese Scholarship Council (to Y. K.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Acknowledgment—The Purdue University Center for Cancer Research is supported by Grant P30 CA023168 from the National Institutes of Health.
©2018The American Society for Biochemistry and Molecular Biology, Inc.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology