IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis

James Vince, W Wei-Ling Wong, Nufail Khan, Rebecca Feltham, Diep Chau, Afsar Ahmed, Christopher Benetatos, Srinivas Chunduru, Stephen Condon, Mark McKinlay, Robert Brink, Martin Leverkus, Vinay Teraonkar, Pascal Schneider, Bernard Callus, Frank Koentgen, David Vaux, John Silke

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805 Citations (Scopus)

Abstract

XIAP prevents apoptosis by binding to and inhibiting caspases, and this inhibition can be relieved by IAP antagonists, such as Smac/DIABLO. IAP antagonist compounds (IACs) have therefore been designed to inhibit XIAP to kill tumor cells. Because XIAP inhibits postmitochondrial caspases, caspase 8 inhibitors should not block killing by IACs. Instead, we show that apoptosis caused by an IAC is blocked by the caspase 8 inhibitor crmA and that IAP antagonists activate NF-kappaB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-kappaB-stimulated production of TNFalpha that killed cells in an autocrine fashion. Inhibition of NF-kappaB reduced TNFalpha production, and blocking NF-kappaB activation or TNFalpha allowed tumor cells to survive IAC-induced apoptosis. Cells treated with an IAC, or those in which cIAP1 was deleted, became sensitive to apoptosis induced by exogenous TNFalpha, suggesting novel uses of these compounds in treating cancer.
Original languageEnglish
Pages (from-to)682 - 693
Number of pages12
JournalCell
Volume131
Issue number4
DOIs
Publication statusPublished - 2007
Externally publishedYes

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