Cyclooxygenase-2 inhibitor nimesulide suppresses telomerase activity by blocking Akt/PKB activation in gastric cancer cell line.
Nonsteroidal antiinflammatory drugs (NSAIDs) have been reported to have antiproliferative effects in neoplastic cells of different origin during the past few decades. We aimed to study the effects of the selective COX-2 inhibitor, nimesulide, on cell viability and telomerase and Akt/PKB activity in the human gastric cancer cell line MKN-45 and to explore the molecular mechanism for the antitumor activity of the selective COX-2 inhibitor. We tested the influence of nimesulide on the gastric cancer cell line MKN-45 in vitro. Trypan blue exclusion was used to determine the cell viability after incubation for 0, 12, 24, and 48 hr in different concentrations of nimesulide 0, 25, 50, 100, 200 microM). After treatment or no treatment with 100 microM nimesulide for 0, 12, 24, or 48 hr in the presence or absence of 300 nM okadaic acid for 2 hr, telomerase and Akt/PKB activity was measured using TRAP PCR-ELISA and nonradioactive IP kinase assays, respectively. In the gastric cancer cell line MKN-45 nimesulide caused a time- and dose-dependent reduction in cell numbers and significantly inhibited telomerase and Akt/PKB activity; the inhibition of telomerase activity was partly associated with the attenuation of Akt/PKB activity. These results demonstrate that the selective COX-2 inhibitor suppresses the telomerase activity of gastric cancer cells, in part by blocking the activation of protein kinase B, which provides a new signaling mechanism responsible for the anticancer effects of the selective COX-2 inhibitor.
Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China. yubaoping62@yahoo.com.cn
Yu
Y
Baoping
Hu
H
Guoyong
Yu
Y
Jieping
Ran
R
Zongxue
Luo
L
Hesheng
D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013274:Stomach Neoplasms / Q000201:enzymology*; D013449:Sulfonamides / Q000494:pharmacology*; D019098:Telomerase / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019098:Telomerase; C012655:nimesulide