title: Heat shock protein 90 inhibitor regulates necroptotic cell death via down-regulation of receptor interacting proteins.
abstract: 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG) acts as an inhibitor of heat shock protein 90 (HSP 90), which serves as a nodal protein of diverse signaling networks leading to a variety of biological implications. HSP90 plays the role of a chaperone for a variety of client proteins including receptor interacting protein 1 (RIP1). Since RIP1 and RIP3 are, respectively, required for zVAD- and tumor necrosis factor alpha (TNFα)-mediated necrotic cell death, we pursued to address the effects of DMAG on receptor-and nonreceptor-mediated necroptotic cell death. DMAG facilitated the degradation of receptor interacting protein 3 (RIP3) as well as RIP1, a known client protein of HSP90, in L929 cells. Consequently, DMAG rendered cells more sensitive to TNFα stimulation while it rescued cells from necrotic cell death caused by zVAD. From this study, we propose that DMAG-downregulated RIP1 can shift cell death typing from necroptosis to apoptosis. In contrast, the protective effect of DMAG on zVAD-induced cytotoxicity could be partly explained by the fact that zVAD mediates cytotoxicity via a RIP1 -dependent route. In summary, functional disruption of HSP90 by DMAG destabilized necroptosis proteins RIP1 and RIP3, which in turn regulated zVAD- and TNFα-induced necroptosis. Therefore, pharmacological modulation of necroptotic cell death through HSP90 could be a promising strategy for overcoming cancer drug resistance or protecting ischemic cell death.
authors.forename: Seung Yeon
authors.initials: SY
authors.lastname: Park
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Shim
authors.forename: Jung-Il
authors.initials: JI
authors.lastname: Chae
authors.forename: Young Sik
authors.initials: YS
authors.lastname: Cho
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D020690:GTPase-Activating Proteins / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051379:Mice; D009336:Necrosis; D009842:Oligopeptides / Q000187:drug effects / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016227:Benzoquinones; D020690:GTPase-Activating Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009842:Oligopeptides; C490620:Ralbp1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D053148:Caspase 3; D053179:Caspase 7