Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates activation of cigarette smoke-induced nuclear factor (NF)-kappaB by suppressing activation of IkappaBalpha kinase in human non-small cell lung carcinoma: correlation with suppression of cyclin D1, COX-2, and matrix metalloproteinase-9.
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-kappaB (NF-kappaB)-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-kappaB activation is not known, although the role of NF-kappaB in regulation of apoptosis, angiogenesis, carcinogenesis, and inflammation is established. In our study, in which we examined DNA binding of NF-kappaB in human lung adenocarcinoma H1299 cells, we found that cigarette smoke condensate (CSC)-induced NF-kappaB activation was persistent up to 24 h, and celecoxib suppressed CSC-induced NF-kappaB 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-kappaB kinase (IkappaB), as examined by immunocomplex kinase assay, IkappaB phosphorylation, and IkappaB degradation was also inhibited. Celecoxib also abrogated CSC-induced p65 phosphorylation and nuclear translocation and NF-kappaB-dependent reporter gene expression. CSC-induced NF-kappaB reporter activity induced by NF-kappaB inducing kinase and IkappaB alpha kinase but not that activated by p65 was also blocked by celecoxib. CSC induced the expression of NF-kappaB-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-kappaB 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-kappaB and NF-kappaB-regulated gene expression, which may contribute to its ability to suppress inflammation, proliferation, and angiogenesis.
Shishodia
Shishir
S
Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Aggarwal
Bharat B
BB
D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000068579:Celecoxib; D019938:Cyclin D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D051550:I-kappa B Kinase; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004273:DNA, Neoplasm; D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D016328:NF-kappa B; D011720:Pyrazoles; D012906:Smoke; D013449:Sulfonamides; D019938:Cyclin D1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D020780:Matrix Metalloproteinase 9; D000068579:Celecoxib