Suppression of RelA/p65 nuclear translocation independent of IκB-α degradation by cyclooxygenase-2 inhibitor in gastric cancer
Copyright policy )Suppression of RelA/p65 nuclear translocation independent of IκB-α degradation by cyclooxygenase-2 inhibitor in gastric cancer
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.
- University of Hong Kong China (People's Republic of)
- Fudan University China (People's Republic of)
- Ruijin Hospital China (People's Republic of)
- Jinshan Hospital of Fudan University China (People's Republic of)
- University of Hong Kong (香港大學) China (People's Republic of)
Anti-Inflammatory Agents, Tetradecanoylphorbol Acetate - Pharmacology, Protein-Serine-Threonine Kinases - Metabolism, NF-KappaB Inhibitor alpha, Genetic - Drug Effects, Transcription, Genetic - Drug Effects, Anti-Inflammatory Agents, Non-Steroidal - Pharmacology, Phosphorylation, Anti-Inflammatory Agents, Non-Steroidal, NF-kappa B, DNA, Neoplasm, Dna, Neoplasm - Metabolism, Isoenzymes - Antagonists & Inhibitors, Active Transport, I-kappa B Kinase, Neoplasm Proteins, Isoenzymes, Anticarcinogenic Agents - Pharmacology, Colonic Neoplasms - Pathology, Colonic Neoplasms, I-kappa B Proteins, Nf-Kappa B - Antagonists & Inhibitors - Metabolism, Transcription, Neoplasm Proteins - Antagonists & Inhibitors, Pyrazoles - Pharmacology, Transcription Factor Rela, Active Transport, Cell Nucleus, Transfection, I-Kappa B Kinase, Aspirin - Pharmacology, Protein Binding - Drug Effects, Anticarcinogenic Agents, Humans, Cyclooxygenase Inhibitors, Enzyme Activation - Drug Effects, Protein Processing, Post-Translational - Drug Effects, Protein Processing, Cyclooxygenase Inhibitors - Pharmacology, Active Transport, Cell Nucleus - Drug Effects, Sulfonamides - Pharmacology, Aspirin, Cyclooxygenase 2 Inhibitors, Membrane Proteins, Dna, Phosphorylation - Drug Effects, Post-Translational - Drug Effects, Enzyme Activation, Cyclooxygenase 2, Prostaglandin-Endoperoxide Synthases, Cell Nucleus - Drug Effects, Tumor Necrosis Factor-Alpha - Pharmacology, Stomach Neoplasms - Pathology, Non-Steroidal - Pharmacology, Neoplasm - Metabolism, I-Kappa B Proteins - Genetics - Metabolism
Anti-Inflammatory Agents, Tetradecanoylphorbol Acetate - Pharmacology, Protein-Serine-Threonine Kinases - Metabolism, NF-KappaB Inhibitor alpha, Genetic - Drug Effects, Transcription, Genetic - Drug Effects, Anti-Inflammatory Agents, Non-Steroidal - Pharmacology, Phosphorylation, Anti-Inflammatory Agents, Non-Steroidal, NF-kappa B, DNA, Neoplasm, Dna, Neoplasm - Metabolism, Isoenzymes - Antagonists & Inhibitors, Active Transport, I-kappa B Kinase, Neoplasm Proteins, Isoenzymes, Anticarcinogenic Agents - Pharmacology, Colonic Neoplasms - Pathology, Colonic Neoplasms, I-kappa B Proteins, Nf-Kappa B - Antagonists & Inhibitors - Metabolism, Transcription, Neoplasm Proteins - Antagonists & Inhibitors, Pyrazoles - Pharmacology, Transcription Factor Rela, Active Transport, Cell Nucleus, Transfection, I-Kappa B Kinase, Aspirin - Pharmacology, Protein Binding - Drug Effects, Anticarcinogenic Agents, Humans, Cyclooxygenase Inhibitors, Enzyme Activation - Drug Effects, Protein Processing, Post-Translational - Drug Effects, Protein Processing, Cyclooxygenase Inhibitors - Pharmacology, Active Transport, Cell Nucleus - Drug Effects, Sulfonamides - Pharmacology, Aspirin, Cyclooxygenase 2 Inhibitors, Membrane Proteins, Dna, Phosphorylation - Drug Effects, Post-Translational - Drug Effects, Enzyme Activation, Cyclooxygenase 2, Prostaglandin-Endoperoxide Synthases, Cell Nucleus - Drug Effects, Tumor Necrosis Factor-Alpha - Pharmacology, Stomach Neoplasms - Pathology, Non-Steroidal - Pharmacology, Neoplasm - Metabolism, I-Kappa B Proteins - Genetics - Metabolism
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