IKKbeta-mediated nuclear factor-kappaB activation attenuates smac mimetic-induced apoptosis in cancer cells.
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-kappaB (NF-kappaB). However, how SM induces NF-kappaB and the role of NF-kappaB in SM-induced cancer cell death has not been well elucidated. We found that effective blockage of NF-kappaB had no detectable effect on SM compound 3 (SMC3)-induced TNF secretion, suggesting that the induction of TNF by SMC3 is independent of NF-kappaB. Conversely, SMC3-induced NF-kappaB 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 SMC3 dramatically reduced c-IAP1 level, it had marginal effect on c-IAP2 expression, TNF-induced RIP modification, NF-kappaB activation, and downstream antiapoptosis NF-kappaB target expression. Furthermore, blocking NF-kappaB by targeting IKKbeta or RelA substantially potentiated SMC3-induced cytotoxicity, suggesting that the NF-kappaB pathway inhibits SMC3-induced apoptosis in cancer cells. Our results show that through TNF autocrine, SM induces an IKKbeta-mediated NF-kappaB activation pathway that protects cancer cells against SM-induced apoptosis, and thus, NF-kappaB blockage could be an effective approach for improving the anticancer value of SM.
Bai
Lang
L
Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive Southeast, Albuquerque, NM 87108, USA.
Chen
Wenshu
W
Chen
Wenjie
W
Wang
Xia
X
Tang
Hong
H
Lin
Yong
Y
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D040761:Biomimetic Materials / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D024101:Mitochondrial Proteins / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D051020:bcl-X Protein; D013482:Superoxide Dismutase; D051550:I-kappa B Kinase