Inhibition of proliferation and induction of autophagy by atorvastatin in PC3 prostate cancer cells correlate with downregulation of Bcl2 and upregulation of miR-182 and p21 [miRNA expression]. Homo sapiens

The epidemiologic association between statin use and decreased risk of advanced prostate cancer suggests that statins may inhibit prostate cancer development and/or progression. Studies were performed to determine the effects of a model statin, atorvastatin (ATO), on the proliferation and differentiation of prostate cancer cells, and to identify possible mechanisms of ATO action. ATO inhibited the in vitro proliferation of both LNCaP and PC3 human prostate cancer cells in dose-dependent fashion. The greater inhibitory activity of ATO in PC3 cells was associated with induction of autophagy in that cell line, as demonstrated by increased expression of LC3-II. miR-182 was consistently upregulated by ATO in PC3 cells, but not in LNCaP cells. ATO upregulation of miR-182 in PC3 cells was p53-independent and was reversed by geranylgeraniol. Transfection of miR-182 inhibitors decreased expression of miR-182 by >98% and attenuated the antiproliferative activity of ATO. miR-182 expression in PC3 cells was also increased in response to stress induced by serum withdrawal, suggesting that miR-182 upregulation can occur due to nutritional stress. Bcl2 and p21 were identified to be potential target genes of miR-182 in PC3 cells. Bcl2 was downregulated and p21 was upregulated in PC3 cells exposed to ATO. These data suggest that miR-182 may be a stress-responsive miRNA that mediates ATO action in prostate cancer cells. Overall design: Gene and miRNA expression in two prostate cancer cell lines treated with Atorvastatin vs. untreated control.

他汀类药物使用与晚期前列腺癌风险降低之间的流行病学关联提示，他汀类或可抑制前列腺癌的发生与/或进展。本研究旨在探究模型他汀类药物阿托伐他汀（atorvastatin, ATO）对前列腺癌细胞增殖与分化的影响，并阐明ATO发挥作用的潜在机制。ATO以剂量依赖性方式在体外抑制LNCaP与PC3这两种人前列腺癌细胞的增殖。ATO对PC3细胞的抑制活性更强，这与该细胞系中自噬的诱导相关，该结论可通过LC3-II表达水平升高得到证实。miR-182在PC3细胞中持续被ATO上调，但在LNCaP细胞中未出现该现象。ATO在PC3细胞中对miR-182的上调作用不依赖p53，且可被香叶基香叶醇逆转。转染miR-182抑制剂可使miR-182的表达水平降低98%以上，并削弱ATO的抗增殖活性。PC3细胞中的miR-182表达在血清剥夺诱导的应激反应中同样升高，提示miR-182的上调可由营养应激引发。研究鉴定出Bcl2与p21为PC3细胞中miR-182的潜在靶基因。在ATO处理的PC3细胞中，Bcl2表达下调而p21表达上调。上述数据表明，miR-182或为一种应激响应型microRNA，可介导ATO在前列腺癌细胞中的作用。总体实验设计：对比经阿托伐他汀处理与未经处理的两种前列腺癌细胞系的基因及microRNA表达水平。