TY - JOUR
T1 - IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis
AU - Vince, J.E.
AU - Wong, W.W-L.
AU - Khan, N.
AU - Feltham, R.
AU - Chau, D.
AU - Ahmed, A.U.
AU - Benetatos, C.A.
AU - Chunduru, S.K.
AU - Condon, S.M.
AU - Mckinlay, M.
AU - Brink, R.
AU - Leverkus, M.
AU - Tergaonkar, V.
AU - Schneider, P.
AU - Callus, Bernard
AU - Koentgen, F.
AU - Vaux, D.L.
AU - Silke, J.
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-κB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-κB-stimulated production of TNFα that killed cells in an autocrine fashion. Inhibition of NF-κB reduced TNFα production, and blocking NF-κB activation or TNFα 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 TNFα, 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-κB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-κB-stimulated production of TNFα that killed cells in an autocrine fashion. Inhibition of NF-κB reduced TNFα production, and blocking NF-κB activation or TNFα 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 TNFα, suggesting novel uses of these compounds in treating cancer.
U2 - 10.1016/j.cell.2007.10.037
DO - 10.1016/j.cell.2007.10.037
M3 - Article
C2 - 18022363
SN - 0092-8674
VL - 131
SP - 682
EP - 693
JO - Cell
JF - Cell
IS - 4
ER -