title: COX-2 inhibitor, NS398, enhances Fas-mediated apoptosis via modulation of the PTEN-Akt pathway in human gastric carcinoma cell lines.
abstract: A variety of human cancer cells are resistant to Fas ligand and anti-Fas antibody induced apoptosis. Previously, we reported that human gastric carcinoma cell lines were resistant to the anti-Fas antibody, CH-11, without interferon-gamma pretreatment in vitro. Cyclooxygenase (COX)-2 is known to be expressed in many human malignancies, and is correlated with tumor progression and resistance to apoptosis. This study examined whether NS398, a COX-2 inhibitor, inhibited cell proliferation and increased Fas-mediated apoptosis in human gastric carcinoma cell lines. Treatment of NS398 inhibited cell proliferation in MKN-45, which expressed the highest level of COX-2 among seven human gastric carcinoma cell lines, in a dose- and time-dependent manner, in contrast to less prominent effects in KATO-III, which expresses no COX-2. Although the treatment of CH-11 induced apoptosis in both cells, the simultaneous treatment of NS398 and CH-11 remarkably induced apoptosis, as confirmed by Hoechst 33258 staining and the terminal deoxynucleotidyl transferase- mediated dUTP-digoxigenin nick-end labeling (TUNEL) method in MKN-45. Flow cytometric analysis also revealed the increased pre-G1 fraction by the simultaneous treatment. The treatment of NS398 induced upregulation of Bad and PTEN, and downregulation of phosphorylated Akt (Thr308). These findings suggest that COX-2 might inhibit Fas-mediated apoptosis in human gastric carcinoma cell lines, especially MKN-45, by modulating PTEN and Akt.
authors.affiliation: Division of Organ Pathology, Department of Microbiology and Pathology, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Honjo
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Osaki
authors.forename: Tonang Dwi
authors.initials: TD
authors.lastname: Ardyanto
authors.forename: Toshiki
authors.initials: T
authors.lastname: Hiramatsu
authors.forename: Noritaka
authors.initials: N
authors.lastname: Maeta
authors.forename: Hisao
authors.initials: H
authors.lastname: Ito
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; C481004:CH-11 anti-fas antibody, human; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; D025521:Tumor Suppressor Proteins; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; 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; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human