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Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma

McCabe, K E; Bacos, Karl LU ; Lu, DH; Delaney, J R; Axelrod, J; Potter, M D; Vamos, M; Wong, Victor W.; Cosford, N D P and Xiang, Rong, et al. (2014) In Cell Death and Disease 5.
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)... (More)

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.

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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
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Cell Death and Disease
volume
5
publisher
Nature Publishing Group
external identifiers
  • scopus:84928013139
ISSN
2041-4889
DOI
10.1038/cddis.2014.448
language
English
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no
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d763479a-acc6-4411-8704-7abe60db33e5
date added to LUP
2017-04-05 15:53:07
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2017-09-03 05:20:55
@article{d763479a-acc6-4411-8704-7abe60db33e5,
  abstract     = {<p>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.</p>},
  articleno    = {e1496},
  author       = {McCabe, K E and Bacos, Karl and Lu, DH and Delaney, J R and Axelrod, J and Potter, M D and Vamos, M and Wong, Victor W. and Cosford, N D P and Xiang, Rong and Stupack, D G},
  issn         = {2041-4889},
  keyword      = {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},
  language     = {eng},
  month        = {10},
  publisher    = {Nature Publishing Group},
  series       = {Cell Death and Disease},
  title        = {Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma},
  url          = {http://dx.doi.org/10.1038/cddis.2014.448},
  volume       = {5},
  year         = {2014},
}