Survivin down-regulation plays a crucial role in 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor-induced apoptosis in cancer
Survivin down-regulation plays a crucial role in 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor-induced apoptosis in cancer
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DOI：
10.1074/jbc.m610350200
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发表时间：
2007-07-06
影响因子：
4.8
通讯作者：
Watanabe, Naoki
中科院分区：
文献类型：
--
作者：
Kaneko, Reiko;Tsuji, Naoki;Watanabe, Naoki
3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂 (HRI) 广泛用于降低高胆固醇血症患者的血清胆固醇。先前的研究表明，HRI 可以诱导结肠癌细胞凋亡。在这项研究中，我们更详细地研究了 HRI 诱导细胞凋亡作用的机制。 HRI 洛伐他汀通过阻断胆固醇合成途径诱导人结肠癌细胞系 SW480 细胞凋亡。抗凋亡分子（包括生存素、XIAP、cIAP-1、cIAP-2、Bcl-2 和 Bcl-X-L）的免疫印迹分析表明，洛伐他汀仅降低生存素表达。 RNA干扰导致的生存素下调诱导细胞凋亡，而生存素过度表达使细胞对洛伐他汀诱导的生长抑制具有抵抗力。这些结果表明生存素下调对洛伐他汀的促凋亡特性有很大贡献。法尼基焦磷酸和香叶基香叶基焦磷酸是胆固醇合成途径中的两种下游中间体，可同时逆转生存素下调和洛伐他汀对 Ras 异戊二烯化的阻断。 Ras 异戊二烯化对于 Ras 介导的信号传导的激活非常重要，包括磷脂酰肌醇 3-激酶 (PI3-激酶)/Akt 途径的激活。 PI3 激酶抑制剂下调 SW480 细胞中的生存素。此外，洛伐他汀还能阻断 Ras 激活和 Akt 磷酸化。我们得出的结论是，生存素下调对于洛伐他汀诱导的癌细胞凋亡至关重要，并且洛伐他汀通过阻断 Ras 异戊二烯化来抑制 Ras 介导的 PI3 激酶激活，从而降低生存素表达。
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HRIs) are widely used to reduce serum cholesterol in patients with hypercholesterolemia. Previous studies have shown that HRIs can induce apoptosis in colon cancer cells. In this study, we investigated the mechanisms underlying the apoptosis-inducing effect of HRIs in greater detail. The HRI lovastatin induced apoptosis in the human colon cancer cell line SW480 by blocking the cholesterol synthesis pathway. Immunoblot analysis of antiapoptotic molecules, including survivin, XIAP, cIAP-1, cIAP-2, Bcl-2, and Bcl-X-L, revealed that only survivin expression was decreased by lovastatin. Survivin down-regulation by RNA interference induced apoptosis, and survivin overexpression rendered the cells resistant to lovastatin-induced growth inhibition. These results indicate that survivin down-regulation contributes substantially to the proapoptotic properties of lovastatin. Farnesyl pyrophosphate and geranylgeranyl pyrophosphate, two downstream intermediates in the cholesterol synthesis pathway, simultaneously reversed survivin down-regulation and the blocking of Ras isoprenylation by lovastatin. Ras isoprenylation is important for the activation of Ras-mediated signaling, including the activation of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway. The PI3-kinase inhibitor down-regulated survivin in SW480 cells. In addition, lovastatin blocked Ras activation and Akt phosphorylation. We conclude that survivin down-regulation is crucial in lovastatin-induced apoptosis in cancer cells and that lovastatin decreases survivin expression by inhibiting Ras-mediated PI3-kinase activation via the blocking of Ras isoprenylation.