Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling
Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling
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DOI：
10.1038/sj.onc.1209117
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发表时间：
2006-02-01
期刊：
影响因子：
8
通讯作者：
Arcaro, A
中科院分区：
文献类型：
--
作者：
Khanzada, UK;Pardo, OE;Arcaro, A
研究3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂辛伐他汀对人小细胞肺癌(SCLC)细胞生长和存活的影响。辛伐他汀可显著抑制基础状态和生长因子刺激的体外小细胞肺癌细胞生长，并诱导细胞凋亡。用辛伐他汀处理的SCLC细胞对化疗药物依托泊苷的作用增敏。此外，辛伐他汀对小细胞肺癌体内生长有抑制作用。这些反应与辛伐他汀抑制干细胞因子(SCF)刺激的细胞外信号调节激酶(ERK)、蛋白激酶B(PKB)和核糖体S6激酶的激活有关。ERK通路的结构性激活足以将小细胞肺癌细胞从辛伐他汀的影响中拯救出来。该药物不直接影响c-Kit的激活或其在脂筏上的定位，但除了能够阻断RAS膜的定位外，它还选择性地在翻译后水平下调H-RAS蛋白水平。RNA干扰(RNAi)下调H-RAS和K-RAS均不影响生长因子对ERK的激活作用，而针对N-RAS的RNAi则抑制ERK、PKB和SCLC细胞的生长。总之，我们的数据表明，用辛伐他汀抑制RAS信号可以有效地干扰人小细胞肺癌细胞的生长和存活。
The impact of the 3-hydroxy-3methylglutaryl CoA reductase inhibitor simvastatin on human small-cell lung cancer (SCLC) cell growth and survival was investigated. Simvastatin profoundly impaired basal and growth factor-stimulated SCLC cell growth in vitro and induced apoptosis. SCLC cells treated with simvastatin were sensitized to the effects of the chemotherapeutic agent etoposide. Moreover, SCLC tumour growth in vivo was inhibited by simvastatin. These responses correlated with the inhibition of stem cell factor (SCF)-stimulated activation of extracellular signal-regulated kinase (Erk), protein kinase B (PKB) and ribosomal S6 kinase by simvastatin. Constitutive activation of the Erk pathway was sufficient to rescue SCLC cell from the effects of simvastatin. The drug did not directly affect activation of c-Kit or its localization to lipid rafts, but in addition to its ability to block Ras membrane localization, it selectively downregulated H-Ras protein levels at the post-translational level. Downregulation of either H- or K-Ras by RNA interference (RNAi) did not impair Erk activation by growth factors, whereas an RNAi specific for N-Ras inhibited activation of Erk, PKB and SCLC cell growth. Together our data demonstrate that inhibiting Ras signalling with simvastatin potently disrupts growth and survival in human SCLC cells.