Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-58129
Vince, J E; Wong, W. Wei-Lynn; Khan, N; Feltham, R; Chau, D; Ahmed, A U; Benetatos, C; Chunduru, S K; Condon, S; McKinlay, M; Brink, R; Leverkus, M; Tergaonkar, V; Schneider, P; Callus, B A; Koentgen, F; Vaux, D L; Silke, J (2007). IAP antagonists target cIAP1 to induce TNFα dependent apoptosis. Cell, 131(4):682-693.
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XIAP prevents apoptosis by binding to and in- hibiting caspases, and this inhibition can be re- lieved by IAP antagonists, such as Smac/DIA- BLO. IAP antagonist compounds (IACs) have therefore been designed to inhibit XIAP to kill tumor cells. Because XIAP inhibits post- mitochondrial 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-kB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-kB-stimulated pro- duction of TNFa that killed cells in an autocrine fashion. Inhibition of NF-kB reduced TNFa pro- duction, and blocking NF-kB activation or TNFa 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 TNFa, suggesting novel uses of these compounds in treating cancer.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Institute of Experimental Immunology|
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Deposited On:||15 Jun 2012 17:45|
|Last Modified:||02 Dec 2013 05:54|
|Publisher:||Cell Press; Elsevier|
|Free access at:||Publisher DOI. An embargo period may apply.|
|Citations:||Web of Science®. Times cited: 372|
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