PPARγ ligand‐induced apoptosis through a p53‐dependent mechanism in human gastric cancer cells

• Published in: Cancer science Vol. 94; no. 4; pp. 338 - 343
• Main Authors: Nagamine, Miho, Okumura, Toshikatsu, Tanno, Satoshi, Sawamukai, Mitsuko, Motomura, Wataru, Takahashi, Nobuhiko, Kongo, Yutaka
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-04-2003; Blackwell; John Wiley & Sons, Inc
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Bisphenol A; Cell Cycle Proteins - metabolism; Cell Division - drug effects; Cell growth; Chromans - pharmacology; Cyclin-Dependent Kinase Inhibitor p27; DNA-Binding Proteins - metabolism; Gastric cancer; Gastroenterology. Liver. Pancreas. Abdomen; Genes, Dominant; Humans; Ligands; Medical sciences; Mutants; p53 Protein; Receptors, Cytoplasmic and Nuclear - metabolism; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Thiazolidinediones - pharmacology; Transcription Factors - metabolism; Transfection; Troglitazone; Tumor Cells, Cultured - metabolism; Tumor Cells, Cultured - pathology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - metabolism; Tumors; Human; Stomach; Nuclear receptor; Malignant tumor; PPAR-γ receptor; TP53 Gene; Cell death; Established cell line; Digestive diseases; Genetics; Gastric disease; Apoptosis; Tumor suppressor gene; Hormonal receptor
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2003.tb01443.x

We have recently demonstrated that the PPARγ 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 apo‐ptotic change was significantly reduced by coincubation with bisphenol A digycidyl ether (BADGE), a synthetic PPARy antagonist, in MKN‐74 cells, suggesting that PPARγ mediates the apo‐ptotic effect of troglitazone. Since KATO‐III lacks the p53 gene, we speculated that p53 might be implicated in the PPARγ 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 ap‐optotic 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 p27Kip1 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 PPARy ligand‐induced apoptosis, but not the cell growth inhibition. (Cancer Sci 2003; 94: 338–343)