IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.

By J. Vince, W. Wong, Nufail R. Khan, R. Feltham, Diep Chau, Afsar U. Ahmed, C. Benetatos, S. Chunduru, S. Condon, M. Mckinlay and 8 more. Cell, 2007

1,143 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9b7b34d7c0d6315889d7ce80483825ec3bab761c

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In Cancer Research

1. Véronique Baud
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3. Ivan Dikic
4. P. Meier
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6. Daniela Hoeller
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In Immunology

1. M. Karin
2. Véronique Baud
3. P. Meier
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In Molecular Biology

1. Ivan Dikic
2. Véronique Baud
3. P. Czabotar
4. Daniela Hoeller
5. M. Karin
6. Fenghe Du
7. P. Meier
8. A. Frew

Citations in the corpus

• The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. (2013, positive): “The Smac mimetic Compound A has been described previously (Vince et al., 2007).”
• The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. (2011, positive): “In the absence of cIAPs, complex-I rapidly dissociates from TNF-R1 and forms complex-IIB, which induces cell death (Bertrand et al., 2008; Gaither et al., 2007; Petersen et al., 2007; Varfolomeev et al., 2007; Vince et al., 2007; Wong et al., 2010).”
• Targeting the ubiquitin system in cancer therapy (2009, background): “These have been shown to induce apoptosis in cancer cells by mechanisms involving NF-κB activation via the non-canonical pathway and the subsequent production of TNF-α, which then triggers cell deat”
• The noncanonical NF‐κB pathway (2012, neutral): “Third, cIAP1 ⁄2 degradation by antagonists induces NIK accumulation and activation of noncanonical NF-jB pathway (31, 32).”