Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics
Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics
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DOI：
10.1038/cr.2015.56
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发表时间：
2015-06-01
期刊：
影响因子：
44.1
通讯作者：
Kim, You-Sun
中科院分区：
文献类型：
--
作者：
Koo, Gi-Bang;Morgan, Michael J.;Kim, You-Sun
受体相互作用蛋白激酶-3(RIP3或RIPK3)是执行“程序性”或“调节性”坏死的细胞器的重要组成部分。在这里，我们发现程序性坏死在许多化疗药物的作用下被激活，并导致化疗诱导的细胞死亡。然而，我们发现，由于RIP3转录起始点附近的基因组甲基化，RIP3在癌细胞中的表达经常被沉默，因此RIP3依赖的MLKL激活和化疗死亡期间下游的程序性坏死在很大程度上受到抑制。然而，使用去甲基化药物治疗可以恢复RIP3的表达，从而以依赖于RIP3的方式提高对化疗药物的敏感性。在85%的乳腺癌患者中，与正常组织相比，RIP3在肿瘤中的表达降低，这表明在肿瘤的生长/发展过程中，RIP3缺陷是积极的选择。由于低甲基化药物在患者中的耐受性相当好，我们建议RIP3缺陷的癌症患者在接受常规化疗之前接受低甲基化药物诱导RIP3表达可能会受益。
Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is an essential part of the cellular machinery that executes "programmed" or "regulated" necrosis. Here we show that programmed necrosis is activated in response to many chemotherapeutic agents and contributes to chemotherapy-induced cell death. However, we show that RIP3 expression is often silenced in cancer cells due to genomic methylation near its transcriptional start site, thus RIP3-dependent activation of MLKL and downstream programmed necrosis during chemotherapeutic death is largely repressed. Nevertheless, treatment with hypomethylating agents restores RIP3 expression, and thereby promotes sensitivity to chemotherapeutics in a RIP3-dependent manner. RIP3 expression is reduced in tumors compared to normal tissue in 85% of breast cancer patients, suggesting that RIP3 deficiency is positively selected during tumor growth/development. Since hypomethylating agents are reasonably well-tolerated in patients, we propose that RIP3-deficient cancer patients may benefit from receiving hypomethylating agents to induce RIP3 expression prior to treatment with conventional chemotherapeutics.