Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-κB activation through inhibition of activation of IκBα kinase and Akt in human non-small cell lung carcinoma:: Correlation with suppression of COX-2 synthesis

The cyclooxygenase 2 (COX-2) inhibitor celecoxib (also called celebrex), approved,for the treatment of colon carcinogenesis, rheumatoid arthritis, and other inflammatory diseases, has been shown to induce apoptosis and inhibit angiogenesis. Because NF-kappaB plays a major role in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation, we postulated that celecoxib modulates NF-kappaB. In the present study, we investigated the effect of this drug on the activation of NF-kappaB by a wide variety of agents. We found that celecoxib suppressed NF-kappaB activation induced by various carcinogens, including TNF, phorbol ester, okadaic acid, LPS, and IL-1beta. Celecoxib inhibited TNF-induced IkappaBalpha kinase activation, leading to suppression of IkappaBalpha phosphorylation and degradation. Celecoxib suppressed both inducible and constitutive NF-kappaB without cell type specificity. Celecoxib also suppressed p65 phosphorylation and nuclear translocation. Akt activation, which is required for TNF-induced NF-kappaB activation, was also suppressed by this drug. Celecoxib also inhibited the TNF-induced interaction of Akt with IkappaBalpha kinase (IKK). Celecoxib abrogated the NF-kappaB-dependent reporter gene expression activated by TNF, TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor 2, NF-kappaB-inducing kinase, and IKK, but not that activated by p65. The COX-2 promoter, which is regulated by NF-kappaB, was also inhibited by celecoxib, and this inhibition correlated with suppression of TNF-induced COX-2 expression. Besides NF-kappaB, celecoxib also suppressed TNF-induced JNK, p38 MAPK, and ERK activation. Thus, overall, our results indicate that celecoxib inhibits NF-kappaB activation through inhibition of IKK and Akt activation, leading to down-regulation of synthesis of COX-2 and other genes needed for inflammation, proliferation, and carcinogenesis.