The MEK/ERK pathway mediates COX-2-selective NSAID-induced apoptosis and induced COX-2 protein expression in colorectal carcinoma cells.
Nonsteroidal antiinflammatory drugs (NSAIDs) can prevent colorectal tumorigenesis in humans and in rodents. In vitro and in vivo studies indicate that one of their principal antineoplastic avenues is the induction of apoptosis. We have shown previously that NS-398, which selectively inhibits cyclooxygenase-2 (COX-2) over cyclooxygenase-1, induces apoptosis of colorectal tumour cells and elevates COX-2 protein expression. Here, we have determined that the extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway mediates these effects of NS-398. Treatment of HT29 colorectal carcinoma cells with 75 microM NS-398 caused activation of ERK-1/-2 but not of the p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases. This was apparent at 24 hr and maintained at 72 hr. U0126, a specific inhibitor of the ERK-activating kinases MEK-1/-2, prevented the activation of ERK induced by NS-398 and blocked the increase in COX-2 protein expression seen when HT29 cells were treated with NS-398 alone. The activation of ERK by NS-398 preceded and accompanied a decrease in attached cell yield and an increase in apoptosis. U0126 dose-dependently protected HT29 cells from these antiproliferative effects of NS-398, indicating an antiproliferative role for sustained ERK-1/-2 activation in response to this NSAID. These results point to a key role for the MEK/ERK signalling pathway in mediating the effects of a COX-2-selective NSAID on colorectal carcinoma cells.
Elder
Douglas J E
DJ
Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol, United Kingdom. douglas.elder@bristol.ac.uk
Halton
Dawn E
DE
Playle
Laura C
LC
Paraskeva
Christos
C
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D002070:Butadienes / Q000494:pharmacology; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000378:metabolism*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002070:Butadienes; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009570:Nitriles; D009578:Nitrobenzenes; D013449:Sulfonamides; C113580:U 0126; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human