Journal Article

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

Tae Jung Jang, Hyeock Joo Kang, Jung Ran Kim and Chang Heon Yang

in Carcinogenesis

Volume 25, issue 10, pages 1853-1858
Published in print October 2004 | ISSN: 0143-3334
Published online October 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh199
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

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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.

Keywords: COX, cyclooxygenase; DR, death receptor; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; MIC-1, macrophage inhibitory cytokine-1; NAG-1, NSAID activated gene; NSAIDs, non-steroidal anti-inflammatory drugs; PARP, poly ADP-ribose polymerase; PBS, phosphate-buffered saline; RT–PCR, reverse transcription–polymerase chain reaction; TBS, Tris-buffered saline; TGF-β, transforming growth factor-β; TRAIL, tumor necrosis factor-related apoptosis inducing ligand

Journal Article.  4451 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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