抑制STAT3增强对吉非替尼耐药的非小细胞肺癌药物敏感性的研究
Improving the drug susceptibility of gefitinib-resistant in non-small cell lung cancer by inhibiting the STAT3 activity
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摘要: 目的:探讨非小细胞肺癌(NSCLC)中表皮生长因子受体T790M突变导致的吉非替尼耐药与信号转导及转录激活因子3(STAT3)的相关性。方法:不同浓度STAT3特异性抑制剂JSI-124处理NSCLC H1975细胞和PC9细胞后,CCK-8法检测细胞抑制率,Western blot法检测蛋白水平表达,RT-PCR法检测相关基因mRNA水平的表达。结果:NSCLC中EGFR T790M突变的H1975细胞中STAT3的表达明显高于PC9细胞(P0.01);JSI-124可剂量和时间依赖性地抑制H1975突变细胞中STAT3的活性,并能增强其对吉非替尼的敏感性。且此现象未在对吉非替尼敏感的PC9细胞中观察到。结论:STAT3因子与表皮生长因子受体T790M突变导致的吉非替尼耐药机制相关,抑制STAT3活性可逆转吉非替尼耐药。Abstract: Objective:To explore the correlation of the drug susceptibility of gefitinib-resistant in non-small cell lung cancer(NSCLS) induced by T790M mutation in EGFR and signal transducers and activators of transcription 3(STAT3).Methods:H1975 and PC9 cells were dealed with different concentrations of STAT3 specific inhibitor JSI-124.The inhibition rate of cells and the levels of protein and mRNA of relative factors were determined by CCK-8,Western blot and RT-PCR,respectirely.Results:The STAT3 expression of H1975 cells with EGFR T790M mutation of NSCLC were obviously higher than that in PC9 cells(P0.01).JSI-124 inhibited the activity of STAT3 in H1975 mutation cells in dose-and time-dependent manner and improved the susceptibility of gefitinib,but not for PC9 cells.Conclusions:The gefitinib-resistant mechanism induced by T790M mutation in EGFR is related to STAT3,which can be reversed by inhibiting the STAT3 activity.
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