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Methylation-Dependent Loss of RIP3 Expression in Cancer Represses Programmed Necrosis in Response to Chemotherapeutics

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dc.contributor.authorKoo, Gi-Bang-
dc.contributor.authorMorgan, Michael J.-
dc.contributor.authorLee, Da-Gyum-
dc.contributor.authorKim, Woo-Jung-
dc.contributor.authorYoon, Jung-Ho-
dc.contributor.authorKoo, Ja Seung-
dc.contributor.authorKim, Seung Il-
dc.contributor.authorKim, Soo Jung-
dc.contributor.authorSon, Mi Kwon-
dc.contributor.authorHong, Soon Sun-
dc.contributor.authorLevy, Jean M. Mulcahy-
dc.contributor.authorPollyea, Daniel A.-
dc.contributor.authorJordan, Craig T.-
dc.contributor.authorYan, Pearlly-
dc.contributor.authorFrankhouser, David-
dc.contributor.authorNicolet, Deedra-
dc.contributor.authorMaharry, Kati-
dc.contributor.authorMarcucci, Guido-
dc.contributor.authorChoi, Kyeong Sook-
dc.contributor.authorCho, Hyeseong-
dc.contributor.authorThorburn, Andrew-
dc.contributor.authorKim, You-Sun-
dc.description.abstractReceptor-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 RIP3 expression is often silenced in cancer cells due to genomic methylation near its transcriptional start site, so 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 when compared to normal tissue in 85% of breast cancer patients, suggesting that RIP3 deficiency is selected for 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.-
dc.titleMethylation-Dependent Loss of RIP3 Expression in Cancer Represses Programmed Necrosis in Response to Chemotherapeuticsen
dc.contributor.departmentDepartment of Biochemistry & Molecular Biology, Ajou University School of Medicine-
dc.contributor.departmentDepartment of Biomedical Sciences, Graduate School of Ajou University-
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