Sustained c-Jun-NH2-kinase activity promotes epithelial-mesenchymal transition, invasion, and survival of breast cancer cells by regulating extracellular signal-regulated kinase activation.
Sustained c-Jun-NH2-kinase activity promotes epithelial-mesenchymal transition, invasion, and survival of breast cancer cells by regulating extracellular signal-regulated kinase activation.
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DOI：
10.1158/1541-7786.mcr-09-0221
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发表时间：
2010-02
期刊：
影响因子：
--
通讯作者：
Cui X
中科院分区：
文献类型：
--
作者：
Wang J;Kuiatse I;Lee AV;Pan J;Giuliano A;Cui X
c-Jun N-末端激酶（JNK）介导应激诱导的细胞凋亡和抗癌治疗的细胞毒性作用。奇怪的是，最近的临床研究表明，在人类乳腺癌中JNK活性升高与预后不良相关。在这里，我们表明，在人乳腺癌细胞中的组成型活性JNK的过度表达并没有引起细胞凋亡，但实际上诱导细胞迁移和侵袭，与上皮间质转化（EMT），间质特异性标志物波形蛋白和纤连蛋白的表达，和AP-1转录因子的活性相关的形态学变化。支持这一观察结果的是，经历EMT的小鼠乳腺肿瘤细胞显示出上调的JNK活性，并且EMT被JNK抑制逆转。持续的JNK活性增强胰岛素受体底物2介导的ERK激活，这反过来又增加了c-Fos表达和AP-1活性。此外，过度活跃的JNK减弱了化疗药物紫杉醇治疗的乳腺癌细胞的凋亡，这与细胞毒性化疗对诱导型JNK活性的要求相反。阻断ERK活性可减少过度活跃的JNK诱导的细胞侵袭和存活。我们的数据表明，JNK的作用变化时，其活性持续升高高于与细胞凋亡相关的基础水平，JNK激活可能作为乳腺癌进展和细胞毒性药物耐药的标志物。
The c-Jun N-terminal kinase (JNK) mediates stress-induced apoptosis and the cytotoxic effect of anticancer therapies. Paradoxically, recent clinical studies indicate that elevated JNK activity in human breast cancer is associated with poor prognosis. Here we show that overexpression of a constitutively active JNK in human breast cancer cells did not cause apoptosis, but actually induced cell migration and invasion, a morphological change associated with epithelial-mesenchymal transition (EMT), expression of mesenchymal-specific markers vimentin and fibronectin, and activity of AP-1 transcription factors. Supporting this observation, mouse mammary tumor cells that have undergone EMT showed upregulated JNK activity, and the EMT was reversed by JNK inhibition. Sustained JNK activity enhanced insulin receptor substrate-2-mediated ERK activation, which in turn increased c-Fos expression and AP-1 activity. In addition, hyperactive JNK attenuated the apoptosis of breast cancer cells treated by the chemotherapy drug paclitaxel, which is in contrast to the requirement for inducible JNK activity in response to cytotoxic chemotherapy. Blockade of ERK activity diminished hyperactive JNK-induced cell invasion and survival. Our data suggest that the role of JNK changes when its activity is elevated persistently above the basal levels associated with cell apoptosis, and that JNK activation may serve as a marker of breast cancer progression and resistance to cytotoxic drugs.