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

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

doi:10.1074/jbc.ra118.004442

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, and HMGCR overexpression 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 the mTOR pathway, 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.

Highlights

hydroxy-3methyl-glutaryl–CoA reductase (HMGCR) was selected for further study because it is the first rate-limiting protein that plays an important role in cholesterol biosynthesis
To validate the findings from our RNA-Seq analysis, a series of Western blotting analyses was performed in LNCaP, MR49F, C4-2, and C4-2R
We found that cholesterol biosynthesis pathway gene set was enriched in high HMGCR-expressing group, indicating that cholesterol biosynthesis pathway was activated as HMGCR expression was elevated (Fig. 1, G and H)

Summary

Introduction

Simvastatin overcomes enzalutamide resistance in vivo experiments showed that statins could significantly reduce the level of prostate-specific antigen (PSA) [12,13,14]. It was reported that such down-regulated PSA levels might be caused by proteolysis of AR induced by statins [15]. All these studies suggest that statins may suppress PCa progression through inhibiting AR. We aim to test whether statins can overcome acquisition of enzalutamide resistance in CRPC, in which AR continues to play an important role.

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Results

Conclusion