title: Accumulation of cytosolic calcium induces necroptotic cell death in human neuroblastoma.
abstract: Necrosis has been studied extensively since the early days of medicine, with some patterns of necrosis found to be programmed like apoptotic cell death. However, mechanisms of programmed necrosis (necroptosis) are yet to be fully elucidated. In this study, we investigated how the hemagglutinating virus of Japan-envelope (HVJ-E) induces necrosis in mouse xenografts of human neuroblastoma cells. HVJ-E-induced necrosis in this system was found to depend on phosphorylation of the death receptor kinase receptor interacting protein kinase 1 (RIP1) and on the production of reactive oxygen species. This process was interpreted as necroptosis, based on its suppression by the small molecule necrostatin-1, and it did not involve the TNF-α receptor pathway. We also demonstrated that increased concentrations of cytoplasmic calcium triggered necroptosis by activating calcium-calmodulin kinase (CaMK) II. Finally, we determined that RIP1 phosphorylation was mediated by CaMK II activation. Together, our results define an upstream pathway for the activation of necroptosis in neuroblastoma cells, with potential therapeutic implications.
authors.affiliation: Authors' Affiliations: Division of Gene Therapy Science and Department of Pediatric Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Motonari
authors.initials: M
authors.lastname: Nomura
authors.forename: Ayumi
authors.initials: A
authors.lastname: Ueno
authors.forename: Kotaro
authors.initials: K
authors.lastname: Saga
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukuzawa
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D002642:Chick Embryo; D003600:Cytosol / Q000378:metabolism*; D000882:Haplorhini; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009336:Necrosis; D009447:Neuroblastoma / Q000473:pathology* / Q000628:therapy*; D018108:Respirovirus; D014407:Tumor Cells, Cultured
chemical_list: D002118:Calcium