Induction mechanism of apoptosis by troglitazone through peroxisome proliferator-activated receptor-gamma in gastric carcinoma cells.

BACKGROUND: It has been reported recently that the antidiabetic thiazolidinediones not only induce fibroblast differentiation but also inhibit the growth of carcinoma cells.

MATERIALS AND METHODS: In the present study, in order to elucidate the further mechanism of growth inhibition by troglitazone, the expression of cell cycle regulators and apoptotic regulators were examined by cDNA microarrays and Western blot analysis by gastric carcinoma cells.

RESULTS: Six gastric carcinoma cell lines (TMK-1, MKN-1,7,28,45,74) were treated with 0.1, 1, 10, 100 microM of troglitazone in vitro. The growth of 5 cell lines were inhibited by troglitazone in a time- and dose-dependent manner. Interestingly, the expression of cyclin D mRNA and protein was decreased and that of p27 was increased in TMK-1 cells at 12 hours after troglitazone treatment, suggesting the induction of cell cycle arrest of the cells. On the other hand, DNA ladder formation was observed at 12 hours after treatment. Moreover, the expression of cytochrome C, caspases 3 and 8 and PARP genes was increased after treatment and the gradual reduction of Bcl-XL protein was observed, which indicate that the apoptotic signals were induced after treatment by troglitazone.

CONCLUSION: These results suggest that the thiazolidinediones can be a new therapeutic tool for gastric carcinoma via cell cycle regulation and apoptosis.