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

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.
AuthorsBenjamin Chun Yu Wong, Xiao hua Jiang, Xiao Ming Fan, Marie Chia Mi Lin, Shi Hu Jiang, Shiu Kum Lam, Hsiang Fu Kung
JournalOncogene (Oncogene) Vol. 22 Issue 8 Pg. 1189-97 (Feb 27 2003) ISSN: 0950-9232 [Print] England
PMID12606945 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 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
Topics
  • 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, metabolism)
  • Isoenzymes (antagonists & inhibitors)
  • Membrane Proteins
  • NF-KappaB Inhibitor alpha
  • NF-kappa B (antagonists & inhibitors, 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)

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