Caffeine inhibits UV-mediated NF-kappaB activation in A2058 melanoma cells: an ATM-PKCdelta-p38 MAPK-dependent mechanism

Mol Cell Biochem. 2008 Jan;308(1-2):193-200. doi: 10.1007/s11010-007-9628-x. Epub 2007 Oct 12.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • Caffeine / pharmacology*
  • Casein Kinase II / metabolism
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Nucleus / radiation effects
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation / drug effects
  • Enzyme Activation / radiation effects
  • Humans
  • I-kappa B Proteins / metabolism
  • Melanoma / enzymology*
  • Melanoma / pathology
  • NF-kappa B / metabolism*
  • Protein Kinase C-delta / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Processing, Post-Translational / drug effects
  • Protein Processing, Post-Translational / radiation effects
  • Protein Transport / drug effects
  • Protein Transport / radiation effects
  • Protein-Serine-Threonine Kinases / metabolism*
  • Transcription Factor RelA / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Suppressor Proteins / metabolism*
  • Ultraviolet Rays*
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • NF-kappa B
  • Protein Kinase Inhibitors
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • Caffeine
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Casein Kinase II
  • Protein-Serine-Threonine Kinases
  • Protein Kinase C-delta
  • p38 Mitogen-Activated Protein Kinases