Differential effects of NF-kappaB on apoptosis induced by DNA-damaging agents: the type of DNA damage determines the final outcome.
The transcription factor nuclear factor kappa-B (NF-kappaB) is generally regarded as an antiapoptotic factor. Accordingly, NF-kappaB activation inhibits death ligand-induced apoptosis. In contrast, ultraviolet light B (UVB)-induced apoptosis is not inhibited but even enhanced upon NF-kappaB activation by interleukin-1 (IL-1). This study was performed to identify the molecular mechanisms underlying this switch of NF-kappaB. Enhancement of UVB-induced apoptosis was always associated with increased release of tumour necrosis factor-alpha (TNF-alpha), which was dependent on NF-kappaB activation. The same was observed when UVA and cisplatin were used, which like UVB induce base modifications. In contrast, apoptosis caused by DNA strand breaks was not enhanced by IL-1, indicating that the type of DNA damage is critical for switching the effect of NF-kappaB on apoptosis. Surprisingly, activated NF-kappaB induced TNF-alpha mRNA expression in the presence of all DNA damage-inducing agents. However, in the presence of DNA strand breaks, there was no release of the TNF-alpha protein, which is so crucial for enhancing apoptosis. Together, this indicates that induction of DNA damage may have a significant impact on biological effects but it is the type of DNA damage that determines the final outcome. This may have implications for the role of NF-kappaB in carcinogenesis and for the application of NF-kappaB inhibitors in anticancer therapy.
Strozyk
E
E
Department of Dermatology, University of Muenster, Muenster, Germany.
Pöppelmann
B
B
Schwarz
T
T
Kulms
D
D
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D019457:Chromosome Breakage; D002945:Cisplatin / Q000633:toxicity; D020552:Comet Assay; D004249:DNA Damage; D004317:Doxorubicin / Q000633:toxicity; D005047:Etoposide / Q000633:toxicity; D005720:Gamma Rays / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000502:physiology; D020672:I-kappa B Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007624:KB Cells / Q000187:drug effects / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D061988:Proteasome Inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology; D014158:Transcription, Genetic / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects*
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000970:Antineoplastic Agents; D020672:I-kappa B Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D007976:Leupeptins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009570:Nitriles; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; C067713:lactacystin; D000072000:NF-KappaB Inhibitor alpha; D005047:Etoposide; D004317:Doxorubicin; D051550:I-kappa B Kinase; D002945:Cisplatin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine