Simvastatin delays castration-resistant prostate cancer metastasis and androgen receptor antagonist resistance by regulating the expression of caveolin-1

The failure of androgen deprivation therapy in prostate cancer treatment mainly results from drug resistance to androgen receptor antagonists. Although an aberrant caveolin-1 (Cav-1) expression has been reported in multiple tumor cell lines, it is unknown whether it is responsible for the progression of castration-resistant prostate cancer (CRPC). Thus, the aim of the present study was to determine whether Cav-1 can be used as a key molecule for the prevention and treatment of CRPC, and to explore its mechanism of action in CRPC. For this purpose, tissue and serum samples from patients with primary prostate cancer and CRPC were analyzed using immunohistochemistry and enzyme-linked immunosorbent assay, which revealed that Cav-1 was overexpressed in CRPC. Furthermore, Kaplan-Meier survival analysis and univariate Cox proportional hazards regression analysis demonstrated that Cav-1 expression in tumors was an independent risk factor for the occurrence of CRPC and was associated with a shorter recurrence-free survival time in patients with CRPC. Receiver operating characteristic curves suggested that serum Cav-1 could be used as a diagnostic biomarker for CRPC (area under the curve, 0.876) using a cut-off value of 0.68 ng/ml (with a sensitivity of 82.1% and specificity of 80%). In addition, it was determined that Cav-1 induced the invasion and migration of CRPC cells by the activation of the H-Ras/phosphoinositide-specific phospholipase C epsilon signaling cascade in the cell membrane caveolae. Importantly, simvastatin was able to augment the anticancer effects of androgen receptor antagonists by downregulating the expression of Cav-1. Collectively, the findings of this study provide evidence that Cav-1 is a promising predictive biomarker for CRPC and that lowering cholesterol levels with simvastatin or interfering with the expression of Cav-1 may prove to be a useful strategy with which to prevent and/or treat CRPC.