Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma

• Published in: Cell death & disease Vol. 5; no. 10; p. e1496
• Main Authors: McCabe, K E, Bacos, K, Lu, D, Delaney, J R, Axelrod, J, Potter, M D, Vamos, M, Wong, V, Cosford, N D P, Xiang, R, Stupack, D G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2014; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/2; 631/67/1059/99; 631/67/1517/1709; 631/80/82/2344; 96; 96/2; 96/44; Antibodies; Apoptosis - drug effects; Autocrine Communication - drug effects; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cisplatin - pharmacology; Cisplatin - therapeutic use; Drug Resistance, Neoplasm - drug effects; Female; Humans; Immunology; Inhibitor of Apoptosis Proteins - antagonists & inhibitors; Inhibitor of Apoptosis Proteins - metabolism; Life Sciences; Mutation - genetics; Necrosis; Oligopeptides - pharmacology; Original; original-article; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - pathology; Phenotype; Protease Inhibitors - pharmacology; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Transcription, Genetic - drug effects; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.448

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
(TNF
α
)-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 TNF
α
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.