title: Anti-gastric cancer effects of celecoxib, a selective COX-2 inhibitor, through inhibition of Akt signaling.
abstract: OBJECTIVE
  Previously, we showed that treatment with celecoxib significantly reduced the number of viable gastric cancer cells, in a dose- and time-dependent manner. However, the specific anti-cancer effects of celecoxib on gastric cancer cells have not been clarified. The present in vitro study was carried out to investigate the mechanism involved in the anti-gastric cancer effects of celecoxib.
  
  
  METHODS
  3-(4,5-Dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was carried out after treating AGS cells (human gastric cancer cell line, ATCC CRL 1739) with celecoxib or indomethacin, and the effect of prostaglandin E(2) or LY294002 (PI3K inhibitor) was evaluated. Western blot analysis of tAkt (total Akt), pAkt (phosphorylated Akt), pGSK3beta (phosphorylated glycogen synthase kinase-3beta), pFKHR (phosphorylated forkhead transcriptional factor), and caspase-9 was carried out at various concentrations (0, 5, 10, 25, or 50 micromol/L) of celecoxib or indomethacin-treatment for 24 or 48 h in AGS cells.
  
  
  RESULTS
  Celecoxib- or LY294002-induced cell death was found to occur in a dose-dependent manner in AGS cells, and these decreases were slightly recovered by the addition of PGE(2) (25 or 50 micromol/L). The expression of pAkt but not tAkt was lower in the celecoxib treated-AGS cells and the response was dose dependent (P < 0.05). The expression of pGSK3beta and pFKHR was also significantly decreased in the celecoxib treated-AGS cells. Procaspase 9 (47 kDa) was frequently cleaved into 37, 35 and 17 kDa fragments in the celecoxib-treatment group. However, these changes in cell signal transduction were not observed in the indomethacin treated-AGS cells.
  
  
  CONCLUSIONS
  The anti-cancer effects of celecoxib on gastric cancer cells might be partly mediated by downregulation of Akt, GSK3beta, FKHR, and upregulation of caspase-9, in the mitochondrial apoptotic pathway.
authors.affiliation: Department of Internal Medicine, Seoul National University, Bundang Hospital, Seongnam, Gyeonggi-do, Seoul, South Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kim
authors.forename: Chung Hyun
authors.initials: CH
authors.lastname: Kim
authors.forename: Dong-Won
authors.initials: DW
authors.lastname: Ahn
authors.forename: Kyoung Soo
authors.initials: KS
authors.lastname: Lee
authors.forename: Soo-Jeong
authors.initials: SJ
authors.lastname: Cho
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Mi Kyoung
authors.initials: MK
authors.lastname: Lee
authors.forename: Joo Sung
authors.initials: JS
authors.lastname: Kim
authors.forename: Hyun Chae
authors.initials: HC
authors.lastname: Jung
authors.forename: In Sung
authors.initials: IS
authors.lastname: Song
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D053453:Caspase 9 / Q000378:metabolism; D000068579:Celecoxib; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D052246:Cyclooxygenase 2 Inhibitors; D051858:Forkhead Transcription Factors; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C506433:CASP9 protein, human; D053453:Caspase 9; D000068579:Celecoxib; D015232:Dinoprostone; D007213:Indomethacin