Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 682 - 693 |
| Number of pages | 12 |
| Journal | Cell |
| Volume | 131 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2007 |
| Externally published | Yes |
Cite this
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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 journal › Article › Research › peer-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.
UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18022363
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 -