Publications

Publication Search

Search for publications by

IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis

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.

Type Journal
ISBN 0092-8674 (Print)
Authors Vince, J. E.;Wong, W. W.;Khan, N.;Feltham, R.;Chau, D.;Ahmed, A. U.;Benetatos, C. A.;Chunduru, S. K.;Condon, S. M.;McKinlay, M.;Brink, R.;Leverkus, M.;Tergaonkar, V.;Schneider, P.;Callus, B. A.;Koentgen, F.;Vaux, D. L.;Silke, J. :
Garvan Authors Prof Robert Brink
Publisher Name CELL
Published Date 2007-01-01 00:00:00
Published Volume 131
Published Issue 4
Published Pages 682-93
URL http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18022363
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?2299_11033/07 Vince Cell.pdf