Dual function of nonsteroidal anti-inflammatory drugs (NSAIDs): inhibition of cyclooxygenase and induction of NSAID-activated gene.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used drugs for the treatment of inflammatory disease and have a chemopreventive effect on colorectal cancer. NSAIDs inhibit cyclooxygenase (COX)-1 and/or COX-2 activity, but the chemopreventive effect may be, in part, independent of prostaglandin inhibition. NSAID-activated gene (NAG-1) was previously identified as a gene induced by some NSAIDs in cells devoid of COX activity. NAG-1 has proapoptotic and antitumorigenic activity in vitro and in vivo. To determine whether the induction of NAG-1 by NSAIDs is influenced by COX expression, we developed COX-1- and COX-2-overexpressing HCT-116 cells. COX expression did not affect NSAID-induced NAG-1 expression as assessed by transient and stable transfection. Also, NAG-1 expression was not affected by PGE(2) and arachidonic acid, suggesting that NAG-1 induction by NSAIDs occurs by a prostanoid-independent manner. We also report that indomethacin increased NAG-1 expression in a number of cells from tissues other than colorectal. In conclusion, NSAIDs have dual function, induction of NAG-1 expression and inhibition of COX activity that occurs in a variety of cell lines.
Baek
Seung Joon
SJ
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Drive, Research Triangle Park, NC 27709, USA.
Wilson
Leigh C
LC
Lee
Chang-Ho
CH
Eling
Thomas E
TE
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics*; D015232:Dinoprostone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D055436:Growth Differentiation Factor 15; D006801:Humans; D007213:Indomethacin; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D007527:Isoenzymes; D008565:Membrane Proteins; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007213:Indomethacin