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Cancer Sci. 2003 Apr;94(4):338-43.

PPAR gamma ligand-induced apoptosis through a p53-dependent mechanism in human gastric cancer cells.

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Third Department of Internal Medicine, Asahikawa Medical College, Asahikawa, Hokkaido 078-8510, Japan.


We have recently demonstrated that the PPAR gamma ligand troglitazone induced cell growth arrest and evoked apoptosis in a gastric cancer cell line, MKN-45. Since in general, p53 plays an important role in the induction of apoptosis and growth inhibition, we tried to clarify whether or not p53 mediates troglitazone-induced apoptosis and growth arrest in gastric cancer cells. Troglitazone increased the number of apoptoic cells in MKN-28, MKN-45 and MKN-74, but not in KATO-III cells. The troglitazone-induced apoptotic change was significantly reduced by coincubation with bisphenol A digycidyl ether (BADGE), a synthetic PPAR gamma antagonist, in MKN-74 cells, suggesting that PPAR gamma mediates the apoptotic effect of troglitazone. Since KATO-III lacks the p53 gene, we speculated that p53 might be implicated in the PPAR gamma ligand-induced apoptosis. Western blot analysis revealed that p53 expression was increased by troglitazone in a time-dependent manner in MKN-74 cells, further suggesting that p53 may mediate the apoptotic process induced by troglitazone. We next established a dominant-negative p53 mutant by stable transfection of p53 mutant into MKN-74 cells. In the dominant-negative p53 mutant cells, troglitazone failed to induce apoptosis, strongly supporting the hypothesis that p53 indeed mediates the process of the troglitazone-induced apoptosis. In the dominant-negative p53 mutant cells, troglitazone significantly induced cell growth arrest and increased expression of p27(Kip1) protein, which is thought to be the key molecule to evoke growth arrest, suggesting that p53 is not involved in the growth inhibition by troglitazone. All these results suggest that p53 mediates the PPAR gamma ligand-induced apoptosis, but not the cell growth inhibition.

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