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

Research output: Contribution to journalArticleResearchpeer-review

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

Cite this

Vince, J., Wong, W. W-L., Khan, N., Feltham, R., Chau, D., Ahmed, A., ... Silke, J. (2007). IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell, 131(4), 682 - 693. https://doi.org/10.1016/j.cell.2007.10.037
Vince, James ; Wong, W Wei-Ling ; Khan, Nufail ; Feltham, Rebecca ; Chau, Diep ; Ahmed, Afsar ; Benetatos, Christopher ; Chunduru, Srinivas ; Condon, Stephen ; McKinlay, Mark ; Brink, Robert ; Leverkus, Martin ; Teraonkar, Vinay ; Schneider, Pascal ; Callus, Bernard ; Koentgen, Frank ; Vaux, David ; Silke, John. / IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. In: Cell. 2007 ; Vol. 131, No. 4. pp. 682 - 693.
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title = "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.",
author = "James Vince and Wong, {W Wei-Ling} and Nufail Khan and Rebecca Feltham and Diep Chau and Afsar Ahmed and Christopher Benetatos and Srinivas Chunduru and Stephen Condon and Mark McKinlay and Robert Brink and Martin Leverkus and Vinay Teraonkar and Pascal Schneider and Bernard Callus and Frank Koentgen and David Vaux and John Silke",
year = "2007",
doi = "10.1016/j.cell.2007.10.037",
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Vince, J, Wong, WW-L, Khan, N, Feltham, R, Chau, D, Ahmed, A, Benetatos, C, Chunduru, S, Condon, S, McKinlay, M, Brink, R, Leverkus, M, Teraonkar, V, Schneider, P, Callus, B, Koentgen, F, Vaux, D & Silke, J 2007, 'IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis' Cell, vol. 131, no. 4, pp. 682 - 693. https://doi.org/10.1016/j.cell.2007.10.037

IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. / Vince, James; Wong, W Wei-Ling; Khan, Nufail; Feltham, Rebecca; Chau, Diep; Ahmed, Afsar; Benetatos, Christopher; Chunduru, Srinivas; Condon, Stephen; McKinlay, Mark; Brink, Robert; Leverkus, Martin; Teraonkar, Vinay; Schneider, Pascal; Callus, Bernard; Koentgen, Frank; Vaux, David; Silke, John.

In: Cell, Vol. 131, No. 4, 2007, p. 682 - 693.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis

AU - Vince, James

AU - Wong, W Wei-Ling

AU - Khan, Nufail

AU - Feltham, Rebecca

AU - Chau, Diep

AU - Ahmed, Afsar

AU - Benetatos, Christopher

AU - Chunduru, Srinivas

AU - Condon, Stephen

AU - McKinlay, Mark

AU - Brink, Robert

AU - Leverkus, Martin

AU - Teraonkar, Vinay

AU - Schneider, Pascal

AU - Callus, Bernard

AU - Koentgen, Frank

AU - Vaux, David

AU - Silke, John

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

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U2 - 10.1016/j.cell.2007.10.037

DO - 10.1016/j.cell.2007.10.037

M3 - Article

VL - 131

SP - 682

EP - 693

JO - Cell

JF - Cell

SN - 0092-8674

IS - 4

ER -