IKKbeta-mediated nuclear factor-kappaB activation attenuates smac mimetic-induced apoptosis in cancer cells.
IKKbeta-mediated nuclear factor-kappaB activation attenuates smac mimetic-induced apoptosis in cancer cells.
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DOI：
10.1158/1535-7163.mct-09-0068
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发表时间：
2009-06
影响因子：
5.7
通讯作者：
Lin Y
中科院分区：
文献类型：
--
作者：
Bai L;Chen W;Chen W;Wang X;Tang H;Lin Y
Smac mimetics (SM) have been recently reported to kill cancer cells through the extrinsic apoptosis pathway mediated by autocrine tumor necrosis factor (TNF). SM also activates nuclear factor κB (NF-κB). However, how SM induces NF-κB and the role of NF-κB in SM-induced cancer cell death has not been well elucidated. We found that effective blockage of NF-κB had no detectable effect on SM compound 3 (SMC3)-induced TNF secretion, suggesting the induction of TNF by SMC3 is independent of NF-κB. Conversely, SMC3-induced NF-κB activation was found to be mediated by autocrine TNF, because this effect of SMC3 was effectively inhibited when TNF was blocked with either a TNF neutralizing antibody or TNF siRNA. In addition, although SMC3 dramatically reduced c-IAP1 level, it had marginal effect on c-IAP2 expression, TNF-induced RIP modification, NF-κB activation, and downstream anti-apoptosis NF-κB target expression. Furthermore, blocking NF-κB by targeting IKKβ or RelA substantially potentiated SMC3-induced cytotoxicity, suggesting that the NF-κB pathway inhibits SMC3-induced apoptosis in cancer cells. Our results demonstrate that through autocrine TNF, SM induces an IKKβ-mediated NF-κB activation pathway that protects cancer cells against SM-induced apoptosis, and thus, NF-κB blockage could be an effective approach for improving the anticancer value of SM.
