Significance of c-MET overexpression in cytotoxic anticancer drug-resistant small-cell lung cancer cells.
Significance of c-MET overexpression in cytotoxic anticancer drug-resistant small-cell lung cancer cells.
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DOI：
10.1111/cas.12447
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发表时间：
2014-08
期刊：
影响因子：
5.7
通讯作者：
Niimi A
中科院分区：
文献类型：
--
作者：
Ozasa H;Oguri T;Maeno K;Takakuwa O;Kunii E;Yagi Y;Uemura T;Kasai D;Miyazaki M;Niimi A
c-MET受体酪氨酸激酶是肝细胞生长因子的受体。近年来，c-MET/肝细胞生长因子信号通路的激活与多种实体肿瘤的不良预后相关，是表皮生长因子受体酪氨酸激酶抑制剂吉非替尼获得性耐药的机制之一。但是c-MET活化和细胞毒性抗癌药物之间的联系还没有得到充分的研究。在这里，我们发现c-MET在细胞毒性抗癌药物耐药的小细胞肺癌细胞中的表达和激活增强。在耐药细胞中，siRNA对c-MET基因的下调c-MET表达或c-MET抑制剂SU11274对c-MET激活的抑制会改变对细胞毒性抗癌药物的抗性。这些结果表明，c-MET过表达可能在细胞毒性抗癌药物获得性耐药中起重要作用。此外，与亲本细胞相比，抗性细胞中c-MET基因位点的数量增加。综上所述，通过增加c-Met基因位点数量而增加c-Met表达是细胞毒性抗癌药物获得性耐药的机制之一。我们的研究结果增加了一种新的策略，即靶向c-MET，以克服小细胞肺癌对细胞毒性药物的耐药性。
The c-MET receptor tyrosine kinase is the receptor for hepatocyte growth factor. Recently, activation of the c-MET/hepatocyte growth factor signaling pathway was associated with poor prognosis in various solid tumors and was one of the mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib. But the link between c-MET activation and the cytotoxic anticancer drug has not been fully examined. Here, we found that the enhanced expression and activation of c-MET in cytotoxic anticancer agent-resistant small-cell lung cancer cells. Downregulation of c-MET expression by siRNA against the c-MET gene or inhibition of c-MET activation by SU11274, a c-MET inhibitor, in the resistant cells altered resistance to the cytotoxic anticancer agent. These results indicated that c-MET overexpression might play an important role in acquired resistance to cytotoxic anticancer drugs. Furthermore, the number of c-MET gene loci was increased in the resistant cells compared to the parental cells. In conclusion, increased c-Met expression through an increase in the number of c-MET gene loci is one of the mechanisms of acquired resistance to cytotoxic anticancer drugs. Our results add a new strategy, the targeting of c-MET, for overcoming resistance to cytotoxic agents in small-cell lung cancer.
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DOI：
10.1165/rcmb.2007-0001oc
发表时间：
2008-05-01
影响因子：
6.4
作者：
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影响因子：
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