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	Soichiro Honjo, Mitsuhiko Osaki, Tonang Dwi Ardyanto, Toshiki Hiramatsu, Noritaka Maeta, Hisao Ito
Journal	DNA and cell biology (DNA Cell Biol) Vol. 24 Issue 3 Pg. 141-7 (Mar 2005) ISSN: 1044-5498 [Print] United States
PMID	15767780 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antibodies Antineoplastic Agents CH-11 anti-fas antibody, human Cyclooxygenase 2 Inhibitors Cyclooxygenase Inhibitors FASLG protein, human Fas Ligand Protein Membrane Glycoproteins Membrane Proteins Nitrobenzenes Proto-Oncogene Proteins Sulfonamides Tumor Suppressor Proteins N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide Cyclooxygenase 2 PTGS2 protein, human Prostaglandin-Endoperoxide Synthases AKT1 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Phosphoric Monoester Hydrolases PTEN Phosphohydrolase PTEN protein, human
Topics	Antibodies (pharmacology) Antineoplastic Agents (pharmacology) Apoptosis (drug effects) Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Cyclooxygenase Inhibitors (pharmacology) Down-Regulation Fas Ligand Protein Flow Cytometry Humans In Situ Nick-End Labeling Membrane Glycoproteins (pharmacology) Membrane Proteins Nitrobenzenes (pharmacology) PTEN Phosphohydrolase Phosphoric Monoester Hydrolases (metabolism) Phosphorylation Prostaglandin-Endoperoxide Synthases (metabolism) Protein Serine-Threonine Kinases (metabolism) Proto-Oncogene Proteins (metabolism) Proto-Oncogene Proteins c-akt Signal Transduction (drug effects) Stomach Neoplasms (metabolism) Sulfonamides (pharmacology) Tumor Cells, Cultured Tumor Suppressor Proteins (metabolism)

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