Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • 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
Externa organisationer
  • University of California
Forskningsområden

Nyckelord

Originalspråkengelska
Artikelnummere1496
TidskriftCell Death and Disease
Volym5
StatusPublished - 2014 okt 30
PublikationskategoriForskning
Peer review utfördJa
Externt publiceradJa