Statin-induced apoptosis via the suppression of ERK1/2 and Akt activation by inhibition of the geranylgeranyl-pyrophosphate biosynthesis in glioblastoma.
Statin-induced apoptosis via the suppression of ERK1/2 and Akt activation by inhibition of the geranylgeranyl-pyrophosphate biosynthesis in glioblastoma.
复制标题
DOI：
10.1186/1756-9966-30-74
复制
发表时间：
2011-08-10
期刊：
影响因子：
--
通讯作者：
Nishida S
中科院分区：
文献类型：
--
作者：
Yanae M;Tsubaki M;Satou T;Itoh T;Imano M;Yamazoe Y;Nishida S
他汀类药物是胆固醇合成中的限速酶3-羟基-3-甲基戊二酰辅酶A还原酶的抑制剂。甲氧丙戊酸途径中这一关键酶的抑制会导致抑制细胞增殖和诱导细胞凋亡。然而，他汀类药物在胶质母细胞瘤中诱导细胞凋亡的分子机制尚不清楚。在本研究中，我们试图阐明他汀类药物诱导C6胶质瘤细胞凋亡的机制。用细胞活力实验评价他汀类药物对C6胶质瘤细胞的细胞毒作用。用活性检测试剂盒检测caspase-3的酶活性。用免疫印迹法检测他汀类药物对信号转导分子的影响。我们发现他汀类药物抑制了细胞的增殖并诱导了细胞的凋亡。我们还观察到caspase-3活性的增加。他汀类药物诱导的细胞凋亡不受焦磷酸法尼基、角鲨烯、泛醌和异戊基腺嘌呤的抑制，但可被香叶基焦磷酸(GGPP)所抑制。此外，他汀类药物还可降低磷酸化细胞外信号调节蛋白1/2(ERK1/2)和Akt的水平。这些结果表明，他汀类药物在抑制GGPP生物合成的同时诱导细胞凋亡，从而降低ERK1/2和Akt的磷酸化水平。本研究结果还表明他汀类药物可作为治疗胶质母细胞瘤的抗癌药物。
Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. The inhibition of this key enzyme in the mevalonate pathway leads to suppression of cell proliferation and induction of apoptosis. However, the molecular mechanism of apoptosis induction by statins is not well understood in glioblastoma. In the present study, we attempted to elucidate the mechanism by which statins induce apoptosis in C6 glioma cells. The cytotoxicity of statins toward the C6 glioma cells were evaluated using a cell viability assay. The enzyme activity of caspase-3 was determined using activity assay kits. The effects of statins on signal transduction molecules were determined by western blot analyses. We found that statins inhibited cell proliferation and induced apoptosis in these cells. We also observed an increase in caspase-3 activity. The apoptosis induced by statins was not inhibited by the addition of farnesyl pyrophosphate, squalene, ubiquinone, and isopentenyladenine, but by geranylgeranyl-pyrophosphate (GGPP). Furthermore, statins decreased the levels of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt. These results suggest that statins induce apoptosis when GGPP biosynthesis is inhibited and consequently decreases the level of phosphorylated ERK1/2 and Akt. The results of this study also indicate that statins could be used as anticancer agents in glioblastoma.
登录
查看更多内容
影响因子：
4.6
作者：
Skottheim, Ine Blankenbery;Gedde-Dahl, Ane;Asbery, Anders
通讯作者：
Asbery, Anders
影响因子：
4.7
作者：
Taylor-Harding, Barbie;Orsulic, Sandra;Li, Andrew J.
通讯作者：
Li, Andrew J.
影响因子：
2.5
作者：
Koyuturk, M;Ersoz, M;Altiok, N
通讯作者：
Altiok, N
影响因子：
5.7
作者：
Tsubaki, Masanobu;Kato, Chisato;Nishida, Shozo
通讯作者：
Nishida, Shozo
影响因子：
11.2
作者：
Wu, JH;Wong, WWL;Penn, LZ
通讯作者：
Penn, LZ