Retaining MKP1 expression and attenuating JNK-mediated apoptosis by RIP1 for cisplatin resistance through miR-940 inhibition.
Retaining MKP1 expression and attenuating JNK-mediated apoptosis by RIP1 for cisplatin resistance through miR-940 inhibition.
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DOI：
10.18632/oncotarget.1798
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发表时间：
2014-03-15
期刊：
影响因子：
--
通讯作者：
Lin Y
中科院分区：
文献类型：
--
作者：
Wang Q;Shi S;He W;Padilla MT;Zhang L;Wang X;Zhang B;Lin Y
阐明化疗耐药机制对提高癌症患者生存率具有重要意义。在这篇报告中，我们研究了受体相互作用蛋白1(RIP1)，一个细胞生存和死亡信号的中介，参与癌症对化疗的反应的作用和机制。在肺癌细胞中，RIP1的敲除显著增加了顺铂诱导的凋亡细胞毒性，这与强大的JNK激活有关。在RIP1基因敲除细胞中，JNK失活磷酸酶mkp1的表达显著减少。尽管RIP1抑制并未改变MKP1蛋白的稳定性，但在RIP1抑制的细胞中，MKP1的合成速率显著降低。此外，我们还发现miR-940在RIP1基因敲除细胞中的表达显著增加。MiR-940基因敲除可恢复Mkp1的表达，并减弱顺铂诱导的JNK活化和细胞毒作用。重要的是，mkp1的异位表达有效地减弱了顺铂诱导的JNK激活和细胞毒作用。此外，在RIP1基因敲除细胞中，JNK上游信号通路MKK4的激活也被增强。总之，我们的结果表明，RIP1通过抑制JNK激活而参与顺铂耐药，JNK激活涉及释放miR-940介导的对MKp1的抑制和对MKK4的激活。针对RIP1/miR-940/mkp1/JNK通路的干预可用于增敏以铂为基础的化疗。
The elucidation of chemoresistance mechanisms is important to improve cancer patient survival. In this report, we investigated the role and mechanism through which receptor-interacting protein 1 (RIP1), a mediator in cell survival and death signaling, participates in cancer's response to chemotherapy. In lung cancer cells, knockdown of RIP1 substantially increased cisplatin-induced apoptotic cytotoxicity, which was associated with robust JNK activation. The expression of the JNK inactivating phosphatase, MKP1, was substantially reduced in RIP1 knockdown cells. Although MKP1 protein stability was not altered by RIP1 suppression, the synthesis rate of MKP1 was dramatically reduced in RIP1-suppressed cells. Furthermore, we found that the expression of miR-940 was substantially increased in RIP1 knockdown cells. Knockdown of miR-940 restored MKP1 expression and attenuated cisplatin-induced JNK activation and cytotoxicity. Importantly, ectopic expression of MKP1 effectively attenuated cisplatin-induced JNK activation and cytotoxicity. In addition, activation of the JNK upstream signaling kinase, MKK4, was also potentiated in RIP1 knockdown cells. Altogether, our results suggest that RIP1 contributes to cisplatin resistance by suppressing JNK activation that involves releasing miR-940-mediated inhibition of MKP1 and suppressing activation of MKK4. Intervention targeting the RIP1/miR-940/MKP1/JNK pathway may be used to sensitize platinum-based chemotherapy.
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