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Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma

Author:
  • K E McCabe
  • Karl Bacos
  • DH Lu
  • J R Delaney
  • J Axelrod
  • M D Potter
  • M Vamos
  • Victor W. Wong
  • N D P Cosford
  • Rong Xiang
  • D G Stupack
Publishing year: 2014-10-30
Language: English
Publication/Series: Cell Death and Disease
Volume: 5
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

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.

Keywords

  • Apoptosis
  • Autocrine Communication
  • Cisplatin
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Mutation
  • Necrosis
  • Oligopeptides
  • Ovarian Neoplasms
  • Phenotype
  • Protease Inhibitors
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha

Other

Published
  • ISSN: 2041-4889
Karl Bacos
E-mail: karl [dot] bacos [at] med [dot] lu [dot] se

Assistant researcher

Diabetes - Epigenetics

+46 40 39 12 19

91-12-022

Jan Waldenströms gata 35, Malmö

36

Lund University Diabetes Centre, CRC, SUS Malmö, Jan Waldenströms gata 35, House 91:12. SE-214 28 Malmö. Telephone: +46 40 39 10 00