Cyclooxygenase (COX)-2 Inhibitor Celecoxib Abrogates Activation of Cigarette Smoke-Induced Nuclear Factor (NF)-κB by Suppressing Activation of I-κB α Kinase in Human Non-Small Cell Lung Carcinoma

Abstract

Cigarette smoke (CS) has been linked to cardiovascular, pulmonary, and malignant diseases. CS-associated malignancies including cancers of the larynx, oral cavity, and pharynx, esophagus, pancreas, kidney, bladder, and lung; all are known to overexpress the nuclear factor-κB (NF-κB)-regulated gene products cyclin D1, cyclooxygenase (COX)-2, and matrix metalloprotease-9. Whether the COX-2 inhibitor, celecoxib, approved for the treatment of colon carcinogenesis and rheumatoid arthritis, affects CS-induced NF-κB activation is not known, although the role of NF-κB in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation is established. In our study, in which we examined DNA binding of NF-κB in human lung adenocarcinoma H1299 cells, we found that cigarette smoke condensate (CSC)-induced NF-κB activation was persistent up to 24 h, and celecoxib suppressed CSC-induced NF-κB activation. Celecoxib was effective even when administered 12 h after CSC treatment. This effect, however, was not cell type-specific. The activation of inhibitory subunit of NF-κB kinase (IκB), as examined by immunocomplex kinase assay, IκB phosphorylation, and IκB degradation was also inhibited. Celecoxib also abrogated CSC-induced p65 phosphorylation and nuclear translocation and NF-κB-dependent reporter gene expression. CSC-induced NF-κB reporter activity induced by NF-κB inducing kinase and IκB α kinase but not that activated by p65 was also blocked by celecoxib. CSC induced the expression of NF-κB-regulated proteins, COX-2, cyclin D1, and matrix metalloproteinase-9, and celecoxib abolished the induction of all three. The COX-2 promoter that is regulated by NF-κB was activated by CSC, and celecoxib suppressed its activation. Overall, our results suggest that chemopreventive effects of celecoxib may in part be mediated through suppression of NF-κB and NF-κB-regulated gene expression, which may contribute to its ability to suppress inflammation, proliferation, and angiogenesis.