Journal article

IAP antagonists target cIAP1 to induce TNF alpha- dependent apoptosis

James E Vince, W Wei-Lynn Wong, Nufail Khan, Rebecca Feltham, Diep Chau, Afsar U Ahmed, Christopher A Benetatos, Srinivas K Chunduru, Stephen M Condon, Mark McKinlay, Robert Brink, Martin Leverkus, Vinay Tergaonkar, Pascal Schneider, Bernard A Callus, Frank Koentgen, David L Vaux, John Silke

Cell | CELL PRESS | Published : 2007

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..

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