RRC ID 41812
Author Wong BC, Jiang Xh, Fan XM, Lin MC, Jiang SH, Lam SK, Kung HF.
Title Suppression of RelA/p65 nuclear translocation independent of IkappaB-alpha degradation by cyclooxygenase-2 inhibitor in gastric cancer.
Journal Oncogene
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.
Volume 22(8)
Pages 1189-97
Published 2003-2-27
DOI 10.1038/sj.onc.1206234
PII 1206234
PMID 12606945
MeSH 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
IF 7.971
Times Cited 62
Human and Animal Cells MKN28(RCB1000)