Suppression of RelA/p65 nuclear translocation independent of IkappaB-alpha degradation by cyclooxygenase-2 inhibitor in gastric cancer

Oncogene. 2003 Feb 27;22(8):1189-97. doi: 10.1038/sj.onc.1206234.

Abstract

Selective cyclooxygenase-2 (COX-2) inhibitors are promising anti-inflammatory drugs with potential antitumor activities. The nuclear factor-kappa B (NF-kappaB) family of proteins is important transcriptional regulators of genes involved in immunity, inflammation, and carcinogenesis. In the present study, we investigated whether and by which molecular mechanism the selective COX-2 inhibitors inhibit NF-kappaB activation in gastric cancer. The effects of SC236 and its derivative, but devoid of COX-2 enzyme inhibition activity on NF-kappaB signaling, were evaluated using electromobility shift, transfection, and reporter gene assay. The translocation of RelA/p65 was investigated using Western blotting and immunocytochemistry. We showed that SC236 suppressed NF-kappaB-mediated gene transcription and binding activity in gastric cancer. This effect occurred through a mechanism independent of cyclooxygenase activity and prostaglandin synthesis. Furthermore, unlike aspirin, SC236 affected neither the phosphorylation, degradation, nor expression of IkappaB-alpha, suggesting that the effects of SC236 are independent of IKK activity and IkappaB-alpha gene transcription. Instead, SC236 worked directly through suppressing nuclear translocation of RelA/p65. It is possible that SC236 directly targets proteins that facilitate the nuclear translocation of NF-kappaB. Our study suggests an important molecular mechanism by which COX-2 inhibitors reduce inflammation and suppress carcinogenesis in gastrointestinal tract.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anticarcinogenic Agents / pharmacology*
  • Aspirin / pharmacology
  • Colonic Neoplasms / pathology*
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology*
  • DNA, Neoplasm / metabolism
  • Enzyme Activation / drug effects
  • Humans
  • I-kappa B Kinase
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Isoenzymes / antagonists & inhibitors*
  • Membrane Proteins
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Neoplasm Proteins / antagonists & inhibitors*
  • Phosphorylation / drug effects
  • Prostaglandin-Endoperoxide Synthases
  • Protein Binding / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Protein Serine-Threonine Kinases / metabolism
  • Pyrazoles / pharmacology*
  • Stomach Neoplasms / pathology*
  • Sulfonamides / pharmacology*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factor RelA
  • Transcription, Genetic / drug effects
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • 4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide
  • Anti-Inflammatory Agents, Non-Steroidal
  • Anticarcinogenic Agents
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • DNA, Neoplasm
  • I-kappa B Proteins
  • Isoenzymes
  • Membrane Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Neoplasm Proteins
  • Pyrazoles
  • Sulfonamides
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Protein Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Tetradecanoylphorbol Acetate
  • Aspirin