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

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Wong BC, Jiang Xh, Fan XM, Lin MC, Jiang SH, Lam SK, Kung HF

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.

PubMed ID

12606945 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Drugs

SC-236

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
SC-236	Nuclear factor NF-kappa-B complex (Protein Group)	Protein group	Humans	Yes	Inhibitor	Details