Role of ERK-BIM and STAT3-Survivin Signaling Pathways in ALK Inhibitor-Induced Apoptosis in EML4-ALK-Positive Lung Cancer
Role of ERK-BIM and STAT3-Survivin Signaling Pathways in ALK Inhibitor-Induced Apoptosis in EML4-ALK-Positive Lung Cancer
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DOI：
10.1158/1078-0432.ccr-10-2798
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发表时间：
2011-04-15
影响因子：
11.5
通讯作者：
Nakagawa, Kazuhiko
中科院分区：
文献类型：
--
作者：
Takezawa, Ken;Okamoto, Isamu;Nakagawa, Kazuhiko
目的：EML4-ALK（棘皮微管相关蛋白样4间变性淋巴瘤激酶）最近被确定为非小细胞肺癌的转化融合基因。本研究的目的是表征EML4-ALK恶性转化的机制。实验设计：我们建立了稳定表达EML4-ALK变体1或3的NIH 3T3细胞，并检测了EML4-ALK下游的信号分子。结果：EML4-ALK的强制表达诱导了细胞外信号调节激酶（ERK）和STAT3的显著激活，但AKT的激活不明显。抑制ERK或STAT3信号通路可导致表达EML4-ALK任意一种变体的细胞增殖显著减弱，表明这些信号通路在肺癌细胞中作用于EML4-ALK的下游。特异性ALK抑制剂TAE684在表达EML4-ALK的NIH 3T3细胞和携带内源性EML4-ALK的H3122人肺癌细胞中诱导细胞凋亡，同时上调Bcl-2家族促凋亡成员BIM和下调凋亡抑制蛋白（IAP）家族成员survivin。BIM的缺失和survivin的过表达均抑制了tae684诱导的细胞凋亡，提示BIM的上调和survivin的下调都参与了tae684诱导的eml4 - alk阳性肺癌细胞的凋亡。此外，我们发现BIM和survivin的表达分别受ERK和STAT3信号通路的独立调控。结论：在eml4 -ALK阳性肺癌细胞中，ALK抑制剂诱导的凋亡既通过抑制ERK信号导致BIM上调，也通过抑制STAT3信号导致survivin下调介导。临床癌症研究；17日(8);2140 - 8。(c) 2011年aacr。
Purpose: EML4-ALK (echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase) was recently identified as a transforming fusion gene in non-small cell lung cancer. The purpose of the present study was to characterize the mechanism of malignant transformation by EML4-ALK.Experimental Design: We established NIH 3T3 cells that stably express variant 1 or 3 of EML4-ALK and examined the signaling molecules that function downstream of EML4-ALK.Results: Forced expression of EML4-ALK induced marked activation of extracellular signal-regulated kinase (ERK) and STAT3, but not that of AKT. Inhibition of ERK or STAT3 signaling resulted in substantial attenuation of the proliferation of cells expressing either variant of EML4-ALK, suggesting that these signaling pathways function downstream of EML4-ALK in lung cancer cells. The specific ALK inhibitor TAE684 induced apoptosis that was accompanied both by upregulation of BIM, a proapoptotic member of the Bcl-2 family, and by downregulation of survivin, a member of the inhibitor of apoptosis protein (IAP) family, in EML4-ALK-expressing NIH 3T3 cells as well as in H3122 human lung cancer cells harboring endogenous EML4-ALK. Depletion of BIM and overexpression of survivin each inhibited TAE684-induced apoptosis, suggesting that both upregulation of BIM and downregulation of survivin contribute to TAE684-induced apoptosis in EML4-ALK-positive lung cancer cells. Furthermore, BIM and survivin expression was found to be independently regulated by ERK and STAT3 signaling pathways, respectively.Conclusions: ALK inhibitor-induced apoptosis is mediated both by BIM upregulation resulting from inhibition of ERK signaling as well as by survivin downregulation resulting from inhibition of STAT3 signaling in EML4-ALK-positive lung cancer cells. Clin Cancer Res; 17(8); 2140-8. (C) 2011 AACR.