title: Non-steroidal anti-inflammatory drug activated gene (NAG-1) expression is closely related to death receptor-4 and -5 induction, which may explain sulindac sulfide induced gastric cancer cell apoptosis.
abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are powerful chemopreventive agents in various cancers. They act by inhibiting cyclooxygenase (COX) activity, or through other mechanisms. NSAID-activated gene (NAG-1) has antitumorigenic and pro-apoptotic activities, but the mechanisms of NAG-1-induced apoptosis are poorly understood. Here we examined whether NAG-1 expression is induced in gastric cancer cells treated with NSAIDs, and the effect of NAG-1 expression on cell death. NAG-1 cDNA was transfected into SNU601 cells, and the relation between the ectopic expression of NAG-1 and death receptor-4 (DR-4) and DR-5 levels was studied. We found that NAG-1 expression was strongly induced in SNU601 cells, which lack endogenous COX-2, by sulindac sulfide, and that this was closely related with increased apoptosis and decreased cell viability. Moreover, temporal expressions of DR-4 and DR-5 induced by sulindac sulfide were similar to that of NAG-1. Most SNU601 cells transfected with NAG-1 cDNA did not survive during expansion. Forced NAG-1 expression significantly induced apoptosis and DR-4 and DR-5 expression. We conclude that NAG-1 expression is closely related to DR-4 and DR-5 induction, which could provide a mechanistic basis for the apoptotic effect of COX inhibitors in gastric cancer cells.
authors.affiliation: Department of Pathology, Dongguk University College of Medicine, Suek-jang Dong 707, Kyongju, Kyongbuk 780-714, Korea. taejung@mail.dongguk.ac.kr
authors.forename: Tae Jung
authors.initials: TJ
authors.lastname: Jang
authors.forename: Hyeock Joo
authors.initials: HJ
authors.lastname: Kang
authors.forename: Jung Ran
authors.initials: JR
authors.lastname: Kim
authors.forename: Chang Heon
authors.initials: CH
authors.lastname: Yang
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055436:Growth Differentiation Factor 15; D006801:Humans; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; D013467:Sulindac; C025462:sulindac sulfide; D011451:Prostaglandin-Endoperoxide Synthases; D020169:Caspases