Department of Urology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
Prostate. 2011 Feb 15;71(3):298-304. doi: 10.1002/pros.21243. Epub 2010 Aug 17.
Statins (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors) are cholesterol-lowering drugs that are widely used to prevent and treat atherosclerotic cardiovascular disease. Recent epidemiological studies suggest that statins reduce serum prostate-specific antigen (PSA) levels and decrease the risk of prostate cancer. In the present study, we determined the molecular mechanisms related to the regulation of PSA, androgen receptor (AR) and cell proliferation in prostate cancer cell lines by statins.
Western blotting, quantitative real-time polymerase chain reaction, cytotoxicity analysis and a cell proliferation assay were used to resolve the regulatory role of statins (mevastatin and simvastatin) in three prostate cancer cell lines, RWPE-1, 22Rv1, and LNCaP.
Western blotting revealed that both mevastatin and simvastatin downregulated AR and PSA protein. However, these statins did not downregulate AR mRNA expression, while they decreased PSA mRNA. The protease inhibitor MG132 inhibited the downregulation of AR protein which suggested that statins decreased AR protein levels by increasing AR proteolysis. Furthermore, statins reduced cell proliferation in AR positive cells but not in AR negative cells, suggesting that statins regulate cell proliferation via AR expression. In addition, cell proliferation assay at various concentrations of dihydrotestosterone (DHT) showed that statins decreased androgen sensitivity in LNCaP cells.
Statins decreased AR protein by proteolysis but not mRNA transcription. The drop in AR levels resulted in a reduction in androgen sensitivity and a decrease in cell proliferation in AR positive prostate cancer cells.
他汀类药物（3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂）是一种降胆固醇药物，广泛用于预防和治疗动脉粥样硬化性心血管疾病。最近的流行病学研究表明，他汀类药物降低了血清前列腺特异性抗原（PSA）水平，并降低了前列腺癌的风险。在本研究中，我们确定了他汀类药物（美伐他汀和辛伐他汀）调节前列腺癌细胞系中 PSA、雄激素受体（AR）和细胞增殖的分子机制。
使用 Western blot、定量实时聚合酶链反应、细胞毒性分析和细胞增殖测定法，解析他汀类药物（美伐他汀和辛伐他汀）在三种前列腺癌细胞系 RWPE-1、22Rv1 和 LNCaP 中的调节作用。
Western blot 显示美伐他汀和辛伐他汀均下调了 AR 和 PSA 蛋白。然而，这些他汀类药物并没有下调 AR mRNA 表达，而是降低了 PSA mRNA。蛋白酶抑制剂 MG132 抑制了 AR 蛋白的下调，这表明他汀类药物通过增加 AR 蛋白水解来降低 AR 蛋白水平。此外，他汀类药物降低了 AR 阳性细胞的细胞增殖，但对 AR 阴性细胞没有影响，这表明他汀类药物通过 AR 表达来调节细胞增殖。此外，在不同浓度的二氢睾酮（DHT）的细胞增殖测定中，他汀类药物降低了 LNCaP 细胞的雄激素敏感性。
他汀类药物通过蛋白水解而不是 mRNA 转录降低了 AR 蛋白水平。AR 水平下降导致雄激素敏感性降低和 AR 阳性前列腺癌细胞增殖减少。
