sulindac-sulfide and Stomach-Neoplasms

The molecular mechanisms underlying the chemopreventive effects of NSAIDs are not well understood and remain the subject of debate. One of the mechanistic possibilities involves alterations in gene expression. We examined gene expression profiles in SNU601 gastric cancer cells treated with sulindac sulfide (50 microM) for 24 hr. Microarray analysis showed that 1.3% (105/8170) of genes were induced or repressed more than 3-fold in cells treated with sulindac sulfide. Seven genes were selected and confirmed by reverse transcription-polymerase chain reaction. Inhibitor of differentiation/DNA binding-1 (Id-1) was downregulated in SNU601 cells treated with sulindac sulfide. Id-1 expression level was decreased dose-dependently by sulindac sulfide. In addition, the expression pattern of Id-1 was inversely related to that of nm23. We also examined Id-1 expression in human gastric cancer tissues and compared it with clinicopathologic parameters to study its biologic role in the cancers. Id-1 was frequently and strongly expressed in gastric cancer tissues compared with that in adjacent nonmetaplastic mucosa. Its immunoreactivity scores were positively correlated to Ki67 labeling indices and tumor progression, and is higher in intestinal type than in diffuse type. In summary, a number of genes, both induced and repressed, could be important in mediating sulindac sulfide-induced cell death in gastric cancer cells. Id-1, one of the repressed genes, is upregulated in gastric cancers and has positive role in tumor progression and histogenesis of intestinal-type cancers.

Topics: Adult; Aged; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Down-Regulation; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Inhibitor of Differentiation Protein 1; Ki-67 Antigen; Lymphatic Metastasis; Male; Middle Aged; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Stomach Neoplasms; Sulindac; Up-Regulation

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.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Caspases; Cyclooxygenase Inhibitors; Cytokines; Gene Expression Regulation, Neoplastic; Growth Differentiation Factor 15; Humans; Prostaglandin-Endoperoxide Synthases; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor; Stomach Neoplasms; Sulindac; Tumor Cells, Cultured