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IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis


Vince, J E; Wong, W Wei-Lynn; 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, David L; Silke, John (2007). IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell, 131(4):682-693.

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 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 production of TNFa that killed cells in an autocrine fashion. Inhibition of NF-kB reduced TNFa production, 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.

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 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 production of TNFa that killed cells in an autocrine fashion. Inhibition of NF-kB reduced TNFa production, 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > General Biochemistry, Genetics and Molecular Biology
Language:English
Date:2007
Deposited On:15 Jun 2012 15:45
Last Modified:07 Feb 2024 02:37
Publisher:Cell Press; Elsevier
ISSN:0092-8674
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.cell.2007.10.037
PubMed ID:18022363