HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2
HMG-CoA reductase inhibitor mevastatin enhances the growth inhibitory effect of butyrate in the colorectal carcinoma cell line Caco-2
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DOI：
10.1093/carcin/22.7.1061
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发表时间：
2001-07-01
期刊：
影响因子：
4.7
通讯作者：
Stein, J
中科院分区：
文献类型：
--
作者：
Wächtershäuser, A;Akoglu, B;Stein, J
美伐他汀是3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶（胆固醇合成中的限速酶）的抑制剂，丁酸盐（一种短链脂肪酸）可降低人结肠癌细胞的增殖并诱导分化。本研究的目的是确定美伐他汀单独或联合丁酸盐对人结肠癌细胞系Caco-2的增殖、细胞周期和凋亡的影响。在本报告中，我们发现美伐他汀联合丁酸盐以剂量和时间依赖的方式协同抑制Caco-2细胞的生长。此外，与美伐他汀孵育24 h后，细胞阻滞在细胞周期的G（1）期，72 h后转换到G（2）/M期，这伴随着细胞周期蛋白依赖性激酶（cdk）4和cdk 6以及细胞周期蛋白DI的下调，而cdk 2和细胞周期蛋白E蛋白水平在美伐他汀处理期间保持不变。细胞周期抑制剂p21和p27显着上调美伐他汀。美伐他汀的促凋亡特性进一步增强共孵育与丁酸，最后，美伐他汀的影响可以逆转通过添加甲羟戊酸，但不是法呢基-或geranylgeranylpyrophosphate，胆固醇合成的中间产物，培养基。这些结果表明，HMG-CoA还原酶抑制剂如美伐他汀可能通过诱导细胞凋亡以及G（0）/G（1）细胞周期阻滞来增强丁酸盐在结肠癌细胞中的抗增殖作用。
Mevastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis, Butyrate, a short-chain fatty acid, reduces proliferation and induces differentiation of human colon cancer cells. The aim of our study was to determine the effect of mevastatin, alone or in combination with butyrate, on proliferation, the cell cycle and apoptosis in the human colorectal carcinoma cell line Caco-2, In this report we show that mevastatin combined with butyrate synergistically suppressed growth of Caco-2 cells in a dose-and time-dependent manner. In addition, incubation with mevastatin arrested cells in the G(1) phase of the cell cycle after 24 h with a switch to the G(2)/M phase after 72 h, This was accompanied by a down-regulation of cyclin-dependent kinases (cdk) 4 and cdk 6 as well as cyclin DI, while cdk 2 and cyclin E protein levels remained unchanged during mevastatin treatment. Cell cycle inhibitors p21 and p27 were significantly upregulated by mevastatin. The proapoptotic properties of mevastatin were further enhanced by co-incubation with butyrate, Lastly, the effects of mevastatin could be reversed by addition of mevalonate, but not farnesyl- or geranylgeranylpyrophosphate, intermediate products of cholesterol synthesis, to the medium. These results suggest that HMG-CoA reductase inhibitors like mevastatin may enhance the antiproliferative effect of butyrate in colon cancer cells via induction of apoptosis together with a G(0)/G(1) cell cycle arrest.