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IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.
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.
Animals, Apoptosis/physiology, Autocrine Communication, Benzoquinones/metabolism, Brefeldin A/metabolism, Caspase 8/antagonists & inhibitors, Caspase 8/metabolism, Cell Line, Enzyme Inhibitors/metabolism, Humans, Inhibitor of Apoptosis Proteins/antagonists & inhibitors, Inhibitor of Apoptosis Proteins/genetics, Intracellular Signaling Peptides and Proteins/metabolism, Lactams, Macrocyclic/metabolism, Mice, Mitochondrial Proteins/metabolism, Molecular Mimicry, NF-kappa B/metabolism, Proteasome Endopeptidase Complex/metabolism, Protein Synthesis Inhibitors/metabolism, Receptors, Tumor Necrosis Factor, Type I/metabolism, Serpins/metabolism, Signal Transduction/physiology, TNF Receptor-Associated Factor 2/genetics, TNF Receptor-Associated Factor 2/metabolism, Tumor Necrosis Factor-alpha/metabolism, Viral Proteins/metabolism
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