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Adenovirus-mediated p53 Gene Transduction Inhibits Telomerase Activity Independent of Its Effects on Cell Cycle Arrest and Apoptosis in Human Pancreatic Cancer Cells¹

Departments of Surgery 1 [M. K., T. O., K. M., H. N., N. S., M. N., M. T.] and Cardiology [H. U.], Kyushu University Faculty of Medicine, and Department of Molecular Biology [M. N.], Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan

Evidence for a relationship between overexpression of wild-type p53 and telomerase activity remains controversial. We investigated whether p53 gene transduction could cause telomerase inhibition in pancreatic cancer cell lines, focusing on the relation of transduction to growth arrest, cell cycle arrest, and apoptotic cell death. The cells were infected with recombinant adenovirus expressing wild-type p53 or p21^WAF1 at a multiplicity of infection of 100 or were continuously exposed to 10 µM VP-16, which is well known to induce apoptosis. Adenovirus-mediated p53 gene transduction caused G₁ cell cycle arrest, apoptosis, and resultant growth inhibition in MIA PaCa-2 cells; the cell number 2 days after infection was 50% of preinfection value, and 13% of the cells were dead. Moreover, the transduction resulted in complete depression of telomerase activity through down-regulation of hTERT mRNA expression. In contrast, p21^WAF1 gene transduction only arrested cell growth and cell cycle at G₁ phase, and VP-16 treatment inhibited cell growth with G₂-M arrest and apoptosis; after treatment, the cell number was 73% of pretreatment, and 12% of the cells were dead. Neither p21^WAF1 gene transduction nor VP-16 treatment caused telomerase inhibition. Similar results were obtained in two other pancreatic cancer cell lines, SUIT-2 and AsPC-1. Thus, our results demonstrate that the p53 gene transduction directly inhibits telomerase activity, independent of its effects on cell growth arrest, cell cycle arrest, and apoptosis.

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