Caffeine (1,3,7-Trimethylxanthine) inhibits UV-mediated NF-kB activation in A2058 melanoma cells

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NF-kB is activated by radiation, cytotoxic drugs, cytokines and several stress conditions. Activation of NF-kB has been implicated in tumor growth, metastasis, apoptosis resistance, inflammatory and acute phase response. Ultraviolet light (UV) induced NF-kB activation is associated with IkB degradation and nuclear translocation of p65/p50 complex. In the present study we show that caffeine specifically inhibits UV-mediated NF-kB activation, but not TNFa mediated NF-kB activation. In the presence of caffeine, degradation of IkB, p65 phosphorylation and nuclear translocation induced by UV is inhibited. Caffeine also inhibited UV-induced NF-kB promoter driven luciferase expression. Since caffeine is known to inhibit PI3KKs and phosphopdiesterase (PDE), we investigated the role of PI3KKs and PDE in UV induced NF-kB activation in order to evaluate the mechanism by which caffeine prevents UV induced NF-kB activation. Our results show that neither PI3KKs (ATM, ATR and DNA-PK) nor PDE is involved in UV induced NF-kB activation. Calphostin c, rottlerin (PKC inhibitors) and SB203580 (p38 MAPK inhibitor), were able to block UV-mediated NF-kB activation. Therefore we evaluated for UV induced PKC activity and phosphorylation p38 MAPK in the presence of caffeine. We observed that caffeine inhibited UV induced PKC activation, further both caffiene and PKC inhibitors were able to block UV induced phosphorylation of p38 MAPK suggesting that PKC is upstream of P38 MAPK and caffeine inhibits UV induced NF-kB activation through PKC dependant p38 MAPK pathway. Results from our study showing inhibitory role of caffeine on UV induced NF-kB activation suggests that caffeine may be used as a chemopreventive agent against UV induced lesions as NF-kB is known to mediate inflammation and tumorigenesis.Funding: ACS & NIH HL071558