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Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics

 Gi-Bang Koo  ;  Michael J Morgan  ;  Da-Gyum Lee  ;  Woo-Jung Kim  ;  Jung-Ho Yoon  ;  Ja Seung Koo  ;  Seung Il Kim  ;  Soo Jung Kim  ;  Mi Kwon Son  ;  Soon Sun Hong  ;  Jean M Mulcahy Levy  ;  Daniel A Pollyea  ;  Craig T Jordan  ;  Pearlly Yan  ;  David Frankhouser  ;  Deedra Nicolet  ;  Kati Maharry  ;  Guido Marcucci  ;  Kyeong Sook Choi  ;  Hyeseong Cho  ;  Andrew Thorburn  ;  You-Sun Kim 
 CELL RESEARCH, Vol.25(6) : 707-725, 2015 
Journal Title
Issue Date
Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology* ; Breast Neoplasms/drug therapy* ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology* ; Cell Survival/drug effects ; DNA Methylation*/drug effects ; Dose-Response Relationship, Drug ; Female ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Necrosis/drug therapy* ; Necrosis/genetics ; Necrosis/metabolism ; Necrosis/pathology* ; Receptor-Interacting Protein Serine-Threonine Kinases/deficiency ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics* ; Structure-Activity Relationship ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
RIP3 (RIPK3) ; MLKL ; programmed necrosis ; chemotherapy ; hypomethylating agents
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.
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1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Koo, Ja Seung(구자승) ORCID logo https://orcid.org/0000-0003-4546-4709
Kim, Seung Il(김승일)
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