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首页> 外文期刊>Cellular Physiology and Biochemistry >Simvastatin inhibits malignant transformation following expression of the Ha-ras oncogene in NIH 3T3 fibroblasts
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Simvastatin inhibits malignant transformation following expression of the Ha-ras oncogene in NIH 3T3 fibroblasts

机译：辛伐他汀抑制NIH 3T3成纤维细胞中Ha-ras癌基因表达后的恶性转化

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In previous studies we have shown that the expression of the transforming Ha-ras oncogene in NIH 3T3 fibroblasts stimulates cellular calcium entry, which triggers oscillatory calcium induced calcium release from internal stores. The intracellular calcium oscillations lead to cytoskeletal remodeling by actin stress fiber depolymerization and activation of the Na+/H+ exchanger thus mediating cell swelling and intracellular alkalosis, both important mitogenic signals. This is evidenced by abrogation of Ha-ras induced growth factor independent cell proliferation by interference with any of these events, i.e. by inhibition of cellular calcium entry or inhibition of the Na+/H+ exchanger. As shown in this study, simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme for cholesterol biosynthesis, is able to prevent these events following the expression of the transforming Ha-ras oncogene. We show, that simvastatin inhibits farnesylation dependent membrane translocation of a CAAX motive bearing yellow fluorescent protein and suppresses Ha-ras stimulated cellular calcium influx, which can be identified as capacitative calcium entry. In addition simvastatin is able to block regulatory volume decrease channels and to suppress the cytoskeletal remodeling, intracellular alkalinization, increase in cell volume and growth factor independent cell proliferation induced by the oncogene. Thus simivastatin is able to prevent crucial cellular events following expression of the transforming Ha-ras oncogene. Copyright (C) 2002 S. Karger AG, Basel. [References: 39]
机译：在以前的研究中，我们表明，NIH 3T3成纤维细胞中转化型Ha-ras癌基因的表达刺激细胞钙进入，从而触发振荡性钙诱导的钙从内部储存区释放。细胞内钙振荡通过肌动蛋白应力纤维解聚和Na + / H +交换子的活化导致细胞骨架重塑，从而介导细胞膨胀和细胞内碱中毒，这都是重要的促有丝分裂信号。通过干扰这些事件中的任何事件，即通过抑制细胞钙的进入或抑制Na + / H +交换子，消除Ha-ras诱导的不依赖生长因子的细胞增殖，可以证明这一点。如本研究所示，辛伐他汀是3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶（胆固醇生物合成的关键酶）的抑制剂，能够在表达Ha-ras致癌基因后阻止这些事件。我们表明，辛伐他汀抑制了带有黄色荧光蛋白的CAAX动机的法尼基化依赖性膜易位，并抑制了Ha-ras刺激的细胞钙内流，该钙内流可被确定为电容性钙进入。另外，辛伐他汀能够阻断调节体积减少通道并抑制由癌基因诱导的细胞骨架重塑，细胞内碱化，细胞体积增加和生长因子依赖性细胞增殖。因此，辛伐他汀能够预防转化的Ha-ras癌基因表达后的关键细胞事件。版权所有（C）2002 S.Karger AG，巴塞尔。 [参考：39]

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