Statin induces apoptosis and cell growth arrest in prostate cancer cells
Statin induces apoptosis and cell growth arrest in prostate cancer cells
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DOI：
10.1158/1055-9965.epi-07-0531
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发表时间：
2008-01-01
影响因子：
3.8
通讯作者：
Xu, Xiao-Chun
中科院分区：
文献类型：
--
作者：
Hoque, Ashraful;Chen, Hongli;Xu, Xiao-Chun
他汀类药物是一类抑制甲羟戊酸途径3-羟基-3-甲基戊二酰-CoA还原酶的限速酶的低分子量药物。他汀类药物已被批准并有效地用于控制高胆固醇血症的临床设置。近年来的研究表明，他汀类药物具有抗肿瘤活性，对人类癌症的预防具有潜在的作用。在这项研究中，我们做了细胞活力，DNA片段，和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记试验，以评估他汀类药物对前列腺癌细胞的作用，并使用蛋白质印迹和RhoA激活试验，以调查潜在的分子作用机制。我们的数据表明，洛伐他汀和辛伐他汀有效地降低细胞活力在三个前列腺癌细胞系（PC 3，DU 145，和LnCap）诱导细胞凋亡和细胞生长停滞在G1期。洛伐他汀和辛伐他汀均诱导caspase-8、caspase-3活化，并在较小程度上诱导caspase-9活化。两种他汀类药物均抑制前列腺癌细胞中Rb、磷酸化Rb、细胞周期蛋白D1、细胞周期蛋白D3、CDK 4和CDK 6的表达，但诱导p21和p27的表达。此外，洛伐他汀和辛伐他汀抑制RhoA活化和c-JUN表达，但不抑制环氧合酶-2表达。我们的数据表明，他汀类药物的抗肿瘤活性是由于诱导细胞凋亡和细胞生长停滞。他汀类药物作用的潜在分子机制是通过RhoA的失活介导的，RhoA的失活反过来诱导半胱天冬酶酶活性和/或G1细胞周期。未来的研究应该集中在检查他汀类药物和其他诱导骨质疏松的药物（例如，环氧合酶-2抑制剂或姜黄素），以评估它们在预防前列腺癌中的功效。
Statins are a class of low molecular weight drugs that inhibit the rate-limiting enzyme of the mevalonate pathway 3-hydroxy-3-methylglutaryl-CoA reductase. Statins have been approved and effectively used to control hypercholesterolemia in clinical setting. Recent study showed statin's antitumor activity and suggested a potential role for prevention of human cancers. In this study, we did cell viability, DNA fragmentation, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays to evaluate the action of statins on prostate cancer cells and used Western blotting and RhoA activation assay to investigate the underlying molecular mechanism of action. Our data showed that lovastatin and simvastatin effectively decreased cell viability in three prostate cancer cell lines (PC3, DU145, and LnCap) by inducing apoptosis and cell growth arrest at G, phase. Both lovastatin and simvastatin induced activation of caspase-8, caspase-3, and, to a lesser extent, caspase-9. Both statins suppressed expression of Rb, phosphorylated Rb, cyclin D1, cyclin D3, CDK4, and CDK6, but induced p21 and p27 expression in prostate cancer cells. Furthermore, lovastatin and simvastatin suppressed RhoA activation and c-JUN expression, but not cyclooxygenase-2 expression. Our data showed that the antitumor activity of statins is due to induction of apoptosis and cell growth arrest. The underlying molecular mechanism of statin's action is mediated through inactivation of RhoA, which in turn induces caspase enzymatic activity and/or G, cell cycle. Future studies should focus on examining statins and other apoptosis-inducing drugs (e.g., cyclooxygenase-2 inhibitors or curcumin) together to assess their efficacy in prevention of prostate cancer.