Koo Gi-Bang, Morgan Michael J, Lee Da-Gyum, Kim Woo-Jung, Yoon Jung-Ho, Koo Ja Seung, Kim Seung Il, Kim Soo Jung, Son Mi Kwon, Hong Soon Sun, Levy Jean M Mulcahy, Pollyea Daniel A, Jordan Craig T, Yan Pearlly, Frankhouser David, Nicolet Deedra, Maharry Kati, Marcucci Guido, Choi Kyeong Sook, Cho Hyeseong, Thorburn Andrew, Kim You-Sun
1] Department of Biochemistry, Ajou University School of Medicine, Suwon 443-380, Korea [2] Department of Biomedical Sciences, Graduate School, Ajou University, Suwon 443-380, Korea.
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Cell Res. 2015 Jun;25(6):707-25. doi: 10.1038/cr.2015.56. Epub 2015 May 8.
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.
受体相互作用蛋白激酶3（RIP3或RIPK3）是执行“程序性”或“调控性”坏死的细胞机制的重要组成部分。在此我们表明，程序性坏死在许多化疗药物作用下被激活，并导致化疗诱导的细胞死亡。然而，我们发现由于RIP3转录起始位点附近的基因组甲基化，癌细胞中RIP3表达常常沉默，因此化疗死亡期间RIP3依赖的混合谱系激酶结构域样蛋白（MLKL）激活及下游程序性坏死在很大程度上受到抑制。尽管如此，用去甲基化剂处理可恢复RIP3表达，从而以RIP3依赖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，肿瘤中RIP3表达降低，这表明在肿瘤生长/发展过程中RIP3缺陷被正向选择。由于去甲基化剂在患者中耐受性较好，我们建议RIP3缺陷的癌症患者可能受益于在接受传统化疗之前先接受去甲基化剂以诱导RIP3表达。
