Journal
MOLECULAR CANCER THERAPEUTICS
Volume 8, Issue 6, Pages 1636-1645Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-09-0068
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- National Cancer Institute/NIH [R03CA125796]
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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-kappa B (NF-kappa B). However, how SM induces NF-kappa B and the role of NF-kappa B in Sm-induced cancer cell death has not been well elucidated. We found that effective blockage of NF-kappa B had no detectable effect on SM compound 3 (SMC3)-induced TNF secretion, suggesting that the induction of TNF by SMC3 is independent of NF-kappa B. Conversely, SMC3-induced NF-kappa B 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 small interfering RNA. In addition, although SIVIC3 dramatically reduced c-IAP1 level, it had marginal effect on c-IAP2 expression, TNF-induced RIP modification, NF-kappa B activation, and downstream antiapoptosis NF-kappa B target expression. Furthermore, blocking NF-kappa B by targeting IKK beta or ReIA substantially potentiated SMC3-induced cytotoxicity, suggesting that the NF-kappa B pathway inhibits SMC3-induced apoptosis in cancer cells. Our results show that through TNF autocrine, SM induces an IKK beta-mediated NF-kappa B activation pathway that protects cancer cells against SM-induced apoptosis, and thus, NF-kappa B blockage could be an effective approach for improving the anticancer value of SM. [Mol Cancer Ther 2009;8(6):1636-45]
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