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B Activation through Inhibition of Activation of IB
Kinase and Akt in Human Non-Small Cell Lung Carcinoma: Correlation with Suppression of COX-2 Synthesis1
Departments of
*
Bioimmunotherapy and
Neuro-Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
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-
B plays a major role in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation, we postulated that celecoxib modulates NF-B. In the present study, we investigated the effect of this drug on the activation of NF-B by a wide variety of agents. We found that celecoxib suppressed NF-B activation induced by various carcinogens, including TNF, phorbol ester, okadaic acid, LPS, and IL-1
. Celecoxib inhibited TNF-induced IB
kinase activation, leading to suppression of IB phosphorylation and degradation. Celecoxib suppressed both inducible and constitutive NF-B without cell type specificity. Celecoxib also suppressed p65 phosphorylation and nuclear translocation. Akt activation, which is required for TNF-induced NF-B activation, was also suppressed by this drug. Celecoxib also inhibited the TNF-induced interaction of Akt with IB kinase (IKK). Celecoxib abrogated the NF-B-dependent reporter gene expression activated by TNF, TNF receptor, TNF receptor-associated death domain, TNF receptor-associated factor 2, NF-B-inducing kinase, and IKK, but not that activated by p65. The COX-2 promoter, which is regulated by NF-B, was also inhibited by celecoxib, and this inhibition correlated with suppression of TNF-induced COX-2 expression. Besides NF-B, celecoxib also suppressed TNF-induced JNK, p38 MAPK, and ERK activation. Thus, overall, our results indicate that celecoxib inhibits NF-B 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.
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