Down-regulation of RIP3 potentiates cisplatin chemoresistance by triggering HSP90-ERK pathway mediated DNA repair in esophageal squamous cell carcinoma
Down-regulation of RIP3 potentiates cisplatin chemoresistance by triggering HSP90-ERK pathway mediated DNA repair in esophageal squamous cell carcinoma
复制标题
RIP3 的下调通过触发食管鳞状细胞癌中 HSP90-ERK 通路介导的 DNA 修复来增强顺铂化疗耐药性。
DOI：
10.1016/j.canlet.2018.01.022
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发表时间：
2018-04-01
期刊：
影响因子：
9.7
通讯作者：
Zhao, Xiaohang
中科院分区：
文献类型：
--
作者：
Sun, Yulin;Zhai, Linhui;Zhao, Xiaohang
受体相互作用蛋白激酶 3 (RIP3) 是程序性坏死细胞死亡的关键调节因子。在这里，我们观察到 RIP3 在食管癌中显着下调。它的剩余表达与更好的化疗反应和延长生存期相关。值得注意的是，激酶死亡的 RIP3 的重新表达也恢复了顺铂敏感性，这表明 RIP3 除了坏死性凋亡之外的一些作用可能与基于顺铂的化疗敏感性有关。为了研究其机制，在顺铂处理 RIP3 敲低细胞后进行了大规模定量蛋白质组学研究。总共大约 7000 个蛋白质组被自信地鉴定出来，蛋白质水平的错误发现率为 0.21%。在这些蛋白质中，685 种表现出 RIP3 依赖性丰度变化。生物信息学分析表明，RIP3 耗尽后 DNA 修复途径受到刺激。功能研究表明，RIP3 缺陷通过激活 HSP90/CDC37 复合物和 ERK 磷酸化在多种细胞系中上调 FOSL1 和 POLD1。此外，通过抑制 HSP90/CDC37 复合物，ERK 和 FOSL1 逆转了顺铂耐药表型。这些结果表明，RIP3 通过原坏死和非坏死功能调节顺铂敏感性。 RIP3可能是预测化疗敏感性的潜在标志物。 (C) 2018 Elsevier B.V. 保留所有权利。
Receptor interacting protein kinase 3 (RIP3) is a critical regulator of programmed necrotic cell death. Here, we observed that RIP3 was significantly down-regulated in esophageal cancer. And its remaining expression was associated with better response to chemotherapy and prolonged survival. Notably, re expression of kinase-dead RIP3 also restored cisplatin sensitivity, suggesting that some roles of RIP3 beyond necroptosis may be involved in cisplatin-based chemosensitivity. To investigate the mechanisms, a large-scale quantitative proteomics study was performed after cisplatin treatment in RIP3-knockdown cells. In total, approximately 7000 protein groups were confidently identified, with a false discovery rate of 0.21% at the protein level. Of these proteins, 685 displayed RIP3-dependent changes in abundance. Bioinformatics analyses indicated that DNA repair pathway was stimulated after RIP3 depletion. Functional studies showed that deficient RIP3 upregulated FOSL1 and POLD1 through activation of the HSP90/CDC37 complex and ERK phosphorylation in multiple cell lines. Furthermore, via inhibition of the HSP90/CDC37 complex, ERK and FOSL1 reversed the cisplatin resistance phenotype. These results suggest that RIP3 regulates cisplatin sensitivity through both pronecrotic and non-necrotic functions. RIP3 may be a potential marker for predicting chemosensitivity. (C) 2018 Elsevier B.V. All rights reserved.