title: COX-2 inhibitors suppress lung cancer cell growth by inducing p21 via COX-2 independent signals.
abstract: COX-2 has been implicated in the control of human non-small cell lung carcinoma (NSCLC) cell growth. The mechanisms by which COX-2 exerts its mitogenic effects have not been entirely elucidated, but stimulation of prostaglandin E2 production and alterations in the expression of the cyclin-dependent kinase inhibitor p21(WAF-1/CIP1/MDA-6)(p2i) have been suggested. Here, we demonstrate that two COX-2 inhibitors (NS398 and Nimesulide) inhibit proliferation and induce apoptosis in NSCLC cells, and these effects were associated with induction of p21 mRNA and protein expression. However, the anti-growth effect of the COX-2 inhibitors and their ability to induce p21 were not affected by COX-2 siRNA suggesting that their actions were COX-2 independent. Instead, activation of the MEK-1/Erk pathway was necessary since COX-2 inhibitors stimulated the phosphorylation of ERKs, and their effects were blocked by PD98095, an inhibitor of this pathway. Furthermore, we show that both NS398 and Nimesulide induced p21 gene promoter activity and this was prevented by PD98095. COX-2 inhibitors increased nuclear protein binding to the Spl site in the promoter region of the p21 gene. Consistent with a role for p21, we found that p21 antisense oligonucleotides prevented the effects of COX-2 inhibitors on cell growth. In summary, our results suggest that COX-2 inhibitors suppress NSCLC cell growth by inducing the expression of the p21 gene through MEK-1/ERK signaling and DNA-protein interactions involving Spl. These observations unveil a mechanism for p21 gene regulation by COX-2 inhibitors in lung carcinoma cell growth and this pathway represents a potential target for therapy.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Whitehead Bioresearch Building, 615 Michael Street, Suite 205-M, Atlanta, GA 30322, USA. shan2@emory.edu
authors.forename: ShouWei
authors.initials: S
authors.lastname: Han
authors.forename: Jesse
authors.initials: J
authors.lastname: Roman
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D048369:MAP Kinase Kinase 1 / Q000187:drug effects; D048748:MAP Kinase Kinase Kinase 3 / Q000187:drug effects; D009578:Nitrobenzenes / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D015689:Oncogene Protein p21(ras) / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D016861:Cyclooxygenase Inhibitors; D005419:Flavonoids; D009578:Nitrobenzenes; D016376:Oligonucleotides, Antisense; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D048748:MAP Kinase Kinase Kinase 3; D048369:MAP Kinase Kinase 1; D015689:Oncogene Protein p21(ras); C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C012655:nimesulide