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.
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Authors | Benjamin Chun Yu Wong, Xiao hua Jiang, Xiao Ming Fan, Marie Chia Mi Lin, Shi Hu Jiang, Shiu Kum Lam, Hsiang Fu Kung |
Journal | Oncogene
(Oncogene)
Vol. 22
Issue 8
Pg. 1189-97
(Feb 27 2003)
ISSN: 0950-9232 [Print] England |
PMID | 12606945
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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