Statin-Induced Autophagy by Inhibition of Geranylgeranyl Biosynthesis in Prostate Cancer PC3 Cells
Statin-Induced Autophagy by Inhibition of Geranylgeranyl Biosynthesis in Prostate Cancer PC3 Cells
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DOI：
10.1002/pros.21131
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发表时间：
2010-06-15
期刊：
影响因子：
2.8
通讯作者：
Yang, Wannian
中科院分区：
文献类型：
--
作者：
Parikh, Ankur;Childress, Chandra;Yang, Wannian
背景自噬是一种在营养胁迫下被激活的大分子和细胞器降解的细胞过程。他汀类药物是胆固醇合成的关键酶3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的一类抑制剂。流行病学研究表明，他汀类药物的使用降低了晚期前列腺癌的发病率。我们探讨了阿托伐他汀（一种治疗高胆固醇血症的常用他汀类药物）治疗诱导前列腺癌细胞自噬的想法。阿托伐他汀诱导的前列腺癌PC 3细胞自噬过程通过免疫印迹和免疫荧光染色检测细胞水平的LC 3-II（一种自噬体标记物）来确定。阿托伐他汀处理PC 3细胞40小时，LC 3-II的表达以剂量依赖性方式增加超过10倍。用胃蛋白酶抑制剂A和E64-d（自噬蛋白酶抑制剂）处理细胞，显著增加阿托伐他汀依赖性LC 3-II表达水平，表明阿托伐他汀诱导自噬通量。此外，阿托伐他汀处理导致PC 3细胞快速死亡。阿托伐他汀诱导的自噬和快速细胞死亡被逆转的香叶基香叶醇，而不是法尼醇，加入到培养基中，表明阿托伐他汀介导的抑制香叶基香叶基生物合成导致自噬和细胞死亡。此外，阿托伐他汀在正常前列腺RWPE 1细胞中不诱导自噬或细胞死亡，在AR阳性前列腺癌LNCaP细胞中仅诱导轻微的自噬反应。我们的研究表明，他汀类药物诱导自噬和自噬相关的细胞死亡的PC 3细胞，可能通过抑制香叶基香叶基化，并表明，自噬反应，他汀类药物可能部分基础的前列腺癌进展的保护作用。重要的是，这些发现强调了他汀类药物可能用于前列腺癌治疗的其他机制。前列腺70：971-981，2010年。(c)2010 Wiley-Liss，Inc.
BACKGROUND. Autophagy is a cellular process of degradation of macromolecules and organelles and activated under nutritional stress. Statins are a class of inhibitors of 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme in synthesis of cholesterol. Epidemiological studies have shown that statin use decreases the incidence of advanced prostate cancer. We explored the idea that treatment of atorvastatin, a commonly prescribed statin for treatment of hypercholesterolemia, induces autophagy in prostate cancer cells.METHODS. The atorvastatin-induced autophagic process in prostate cancer PC3 cells was determined by detection of cellular level of LC3-II, an autophagosomal marker, via immunoblotting and immunofluorescent staining.RESULTS. Atorvastatin treatment of PC3 cells for 40 hrs increased expression of LC3-II by more than 10 fold in a dose-dependent manner. Treatment of the cells with pepstatin A and E64-d, the autophagic protease inhibitors, dramatically increased atorvastatin-dependent LC3-II expression level, suggesting that atorvastatin induces autophagic flux. In addition, atorvastatin treatment caused rapid death of PC3 cells. Atorvastatin-induced autophagy and rapid cell death were reversed by addition of geranylgeraniol, not farnesol, into culture medium, indicating that atorvastatin-mediated inhibition of geranylgeranyl biosynthesis causes autophagy and cell death. Furthermore, atorvastatin did not induce autophagy or cell death in normal prostate RWPE1 cells, and induced only a minor autophagic response in AR-positive prostate cancer LNCaP cells.CONCLUSIONS. Our studies demonstrate that statins induce autophagy and autophagy-associated cell death in PC3 cells, likely through inhibition of geranylgeranylation, and suggest that autophagic response to statins may partially underlie the protective effects of statins on prostate cancer progression. Importantly, these findings highlight additional mechanisms by which statins might be used for prostate cancer therapy. Prostate 70: 971-981, 2010. (c) 2010 Wiley-Liss, Inc.