title: Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma.
abstract: Ovarian cancer patients are typically treated with carboplatin and paclitaxel, but suffer a high rate of relapse with recalcitrant disease. This challenge has fostered the development of novel approaches to treatment, including antagonists of the 'inhibitor of apoptosis proteins' (IAPs), also called SMAC mimetics, as apoptosis-inducing agents whose action is opposed by caspase inhibitors. Surprisingly, IAP antagonist plus caspase inhibitor (IZ) treatment selectively induced a tumor necrosis factor-α (TNFα)-dependent death among several apoptosis-resistant cell lines and patient xenografts. The induction of necroptosis was common in ovarian cancer, with expression of catalytically active receptor-interacting protein kinase-3 (RIPK3) necessary for death, and in fact sufficient to compromise survival of RIPK3-negative, necroptosis-resistant ovarian cancer cells. The formation of a necrosome-like complex with a second critical effector, receptor-interacting serine-threonine kinase-1 (RIPK1), was observed. RIPK1, RIPK3 and TNFα were required for the induction of death, as agents that inhibit the function of any of these targets prevented cell death. Abundant RIPK3 transcript is common in serous ovarian cancers, suggesting that further evaluation and targeting of this RIPK3-dependent pathway may be of clinical benefit.
authors.affiliation: Department of Reproductive Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: McCabe
authors.affiliation: Department of Reproductive Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Bacos
authors.affiliation: 1] Department of Reproductive Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA [2] Nankai University School of Medicine, Tianjin, China.
authors.forename: D
authors.initials: D
authors.lastname: Lu
authors.affiliation: Department of Reproductive Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Delaney
authors.affiliation: Department of Reproductive Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Axelrod
authors.affiliation: Department of Reproductive Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Potter
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Vamos
authors.affiliation: Department of Reproductive Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Wong
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: N D P
authors.initials: ND
authors.lastname: Cosford
authors.affiliation: Nankai University School of Medicine, Tianjin, China.
authors.forename: R
authors.initials: R
authors.lastname: Xiang
authors.affiliation: Department of Reproductive Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Stupack
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D019898:Autocrine Communication / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009336:Necrosis; D009842:Oligopeptides / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D010641:Phenotype; D011480:Protease Inhibitors / Q000494:pharmacology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D002945:Cisplatin