title: Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics.
abstract: 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.
authors.affiliation: 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.
authors.forename: Gi-Bang
authors.initials: GB
authors.lastname: Koo
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morgan
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Suwon 443-380, Korea.
authors.forename: Da-Gyum
authors.initials: DG
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Woo-Jung
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Jung-Ho
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Ja Seung
authors.initials: JS
authors.lastname: Koo
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Seung Il
authors.initials: SI
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 402-751, Korea.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 402-751, Korea.
authors.forename: Mi Kwon
authors.initials: MK
authors.lastname: Son
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 402-751, Korea.
authors.forename: Soon Sun
authors.initials: SS
authors.lastname: Hong
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora 80045, CO 80045, USA.
authors.forename: Jean M Mulcahy
authors.initials: JM
authors.lastname: Levy
authors.affiliation: Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Pollyea
authors.affiliation: Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.affiliation: Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Pearlly
authors.initials: P
authors.lastname: Yan
authors.affiliation: Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: David
authors.initials: D
authors.lastname: Frankhouser
authors.affiliation: 1] Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA [2] Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Deedra
authors.initials: D
authors.lastname: Nicolet
authors.affiliation: 1] Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA [2] Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.affiliation: Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: 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.
authors.forename: Kyeong Sook
authors.initials: KS
authors.lastname: Choi
authors.affiliation: 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.
authors.forename: Hyeseong
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Thorburn
authors.affiliation: 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.
authors.forename: You-Sun
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009336:Necrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases