Afatinib induces apoptosis in NSCLC without EGFR mutation through Elk-1-mediated suppression of CIP2A.
Afatinib induces apoptosis in NSCLC without EGFR mutation through Elk-1-mediated suppression of CIP2A.
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DOI：
10.18632/oncotarget.2941
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发表时间：
2015-02-10
期刊：
影响因子：
--
通讯作者：
Chen KF
中科院分区：
文献类型：
--
作者：
Chao TT;Wang CY;Chen YL;Lai CC;Chang FY;Tsai YT;Chao CH;Shiau CW;Huang YC;Yu CJ;Chen KF
阿法替尼对表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）具有抗肿瘤作用。我们发现阿法替尼也可以通过CIP 2A途径诱导无EGFR突变的NSCLC细胞凋亡。使用阿法替尼处理4种NSCLC细胞系（H358、H441、H460和A549），以确定其对阿法替尼诱导的细胞死亡和细胞凋亡的敏感性。通过分别在敏感细胞和耐药细胞中过表达和敲低CIP 2A表达，证实了CIP 2A对阿法替尼诱导的细胞凋亡的影响。分析了Elk-1与CIP 2A启动子结合的减少和CIP 2A转录的抑制。还在裸鼠中测定了阿法替尼对H358和H460异种移植瘤的体内疗效。阿法替尼在H358和H441细胞中诱导了显著的细胞死亡和凋亡，但在H460或A549细胞中未诱导。阿法替尼在敏感细胞中的凋亡作用与CIP 2A下调、PP 2A活性促进和AKT磷酸化降低相关。阿法替尼通过降低Elk-1的启动子结合活性，在基因转录水平上抑制CIP 2A。临床样本显示，CIP 2A高表达预示预后不良，Elk-1和CIP 2A表达高度相关。总之，阿法替尼通过Elk-1/CIP 2A/PP 2A/AKT途径诱导无EGFR突变的NSCLC细胞凋亡。
Afatinib has anti-tumor effect in non-small cell lung carcinoma (NSCLC) with epidermal growth factor receptor (EGFR) mutation. We found afatinib can also induce apoptosis in NSCLC cells without EGFR mutation through CIP2A pathway. Four NSCLC cell lines (H358 H441 H460 and A549) were treated with afatinib to determine their sensitivity to afatinib-induced cell death and apoptosis. The effects of CIP2A on afatinib-induced apoptosis were confirmed by overexpression and knockdown of CIP2A expression in the sensitive and resistant cells, respectively. Reduction of Elk-1 binding to the CIP2A promoter and suppression of CIP2A transcription were analyzed. In vivo efficacy of afatinib against H358 and H460 xenografts tumors were also determined in nude mice. Afatinib induced significant cell death and apoptosis in H358 and H441 cells, but not in H460 or A549 cells. The apoptotic effect of afatinib in sensitive cells was associated with downregulation of CIP2A, promotion of PP2A activity and decrease in AKT phosphorylation. Afatinib suppressed CIP2A at the gene transcription level by reducing the promoter binding activity of Elk-1. Clinical samples showed that higher CIP2A expression predicted a poor prognosis and Elk-1 and CIP2A expressions were highly correlated. In conclusion, afatinib induces apoptosis in NSCLC without EGFR mutations through Elk-1/CIP2A/PP2A/AKT pathway.
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影响因子：
158.5
作者：
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通讯作者：
Haber, DA
影响因子：
45.3
作者：
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影响因子：
11.5
作者：
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影响因子：
51.1
作者：
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Esteban Gonzalez, Emilio
DOI：
10.1093/jnci/djn389
发表时间：
2008-12-03
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Jemal A;Thun MJ;Ries LA;Howe HL;Weir HK;Center MM;Ward E;Wu XC;Eheman C;Anderson R;Ajani UA;Kohler B;Edwards BK
通讯作者：
Edwards BK