Caffeine inhibits UV-mediated NF-kappaB activation in A2058 melanoma cells: an ATM-PKCdelta-p38 MAPK-dependent mechanism.
Mammalian ultraviolet (UV) radiation response is a gene induction cascade activated by several transcription factors, including NF-kappaB. Although NF-kappaB is induced by UV radiation, the signal transduction mechanism remains relatively unclear. In the present study, we show that UV-induced NF-kappaB activation is mediated by the activation of Ataxia telangiecia mutated (ATM) and protein kinase C (PKC). We also show that caffeine specifically inhibits UV-mediated NF-kappaB activation, but not TNFalpha-mediated NF-kappaB activation. In addition, our study shows that ATM, but not ATM-Rad3-related (ATR) or DNA-dependent protein kinase (DNA-PK) is involved in UV-induced NF-kappaB activation. Because SB203580 (a p38 MAPK inhibitor), or Calphostin C or rottlerin (PKC inhibitors) was able to inhibit UV-mediated NF-kappaB activation, we evaluated whether caffeine could inhibit p38 MAPK or PKC activity. Caffeine or rottlerin inhibited UV-induced phosphorylation of p38 MAPK, but not anisomycin-induced phosphorylation of p38 MAPK, suggesting that p38 MAPK is downstream of PKC. Additionally, caffeine could effectively inhibit UV-induced increases in PKC activity. Taken together, our study demonstrates that caffeine is a potent inhibitor of UV-induced NF-kappaB activation. Additionally, this inhibition occurs due to the inhibitory action of caffeine on ATM and PKC, resulting in the inhibition of p38 MAPK activation.
Ravi
Dashnamoorthy
D
Department of Pathology, University of Arkansas for Medical Sciences, 4301 W Markham Street, Slot # 845, Little Rock, AR 72205, USA.
Muniyappa
Harish
H
Das
Kumuda C
KC
D064007:Ataxia Telangiectasia Mutated Proteins; D002110:Caffeine / Q000494:pharmacology*; D047390:Casein Kinase II / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000528:radiation effects; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D002110:Caffeine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases