Differential effects of NF-κB on apoptosis induced by DNA-damaging agents:: the type of DNA damage determines the final outcome

The transcription factor nuclear factor kappa-B ( NF-kB) is generally regarded as an antiapoptotic factor. Accordingly, NF-kB activation inhibits death ligand-induced apoptosis. In contrast, ultraviolet light B (UVB)-induced apoptosis is not inhibited but even enhanced upon NF-kappa B activation by interleukin-1 (IL-1). This study was performed to identify the molecular mechanisms underlying this switch of NF-kappa B. Enhancement of UVB-induced apoptosis was always associated with increased release of tumour necrosis factor-alpha (TNF-alpha), which was dependent on NF-kappa B activation. The same was observed when UVA and cisplatin were used, which like UVB induce base modi. cations. 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-kappa B on apoptosis. Surprisingly, activated NF-kappa B 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-kappa B in carcinogenesis and for the application of NF-kappa B inhibitors in anticancer therapy.