Involvement of endoplasmic reticulum stress in Docetaxel-induced JNK-dependent apoptosis of human melanoma
Involvement of endoplasmic reticulum stress in Docetaxel-induced JNK-dependent apoptosis of human melanoma
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DOI：
10.1007/s10495-008-0276-8
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发表时间：
2008-12-01
期刊：
影响因子：
7.2
通讯作者：
Hersey, Peter
中科院分区：
文献类型：
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作者：
Mhaidat, Nizar M.;Thorne, Rick;Hersey, Peter
我们以前的研究表明多西他赛诱导的黑色素瘤细胞凋亡完全依赖于JNK信号通路的激活。在这里，我们表明多西他赛诱导的细胞凋亡是通过诱导ER应激介导的。这通过多西他赛诱导的参与ER应激信号传导的蛋白质即GRP 78、ATF 6、IRE 1 α和PERK/eIF 2 α的活化来显示。通过siRNA敲低IRE 1 α显著抑制多西他赛诱导的JNK激活和JNK下游靶点，表明IRE 1 α的激活在JNK激活的上游。免疫共沉淀实验表明，JNK的激活是由于通过形成IRE 1 α-TRAF 2-ASK 1复合物激活ASK 1。ER应激介导的JNK途径活化是PKC δ活化的下游，因为使用特异性PKC δ siRNA下调PKC δ表达显著抑制多西他赛诱导的IRE 1 α和JNK途径活化。这些发现为了解紫杉烷类药物治疗人类黑色素瘤的作用机制提供了新的见解。
Our previous studies revealed that Docetaxel-induced apoptosis of melanoma cells is entirely dependent on activation of the JNK signalling pathway. Here, we show that Docetaxel-induced apoptosis is mediated by induction of ER stress. This was shown by Docetaxel-induced activation of proteins involved in ER stress signalling namely GRP78, ATF6, IRE1 alpha, and PERK/eIF2 alpha. Knockdown of IRE1 alpha by siRNA markedly inhibited Docetaxel-induced JNK activation and downstream targets of JNK indicating that activation of IRE1 alpha was upstream of activation of the JNK. Co-immunoprecipitation experiments showed that activation of JNK is due to activation of ASK1 through formation of an IRE1 alpha-TRAF2-ASK1 complex. ER stress mediated activation of the JNK pathway is downstream of activation of PKC delta in that downregulation of PKC delta expression using specific PKC delta siRNA significantly inhibited Docetaxel-induced activation of IRE1 alpha and the JNK pathway. These findings provide new insights to understand the mode of action of taxanes in treatment of human melanoma.