p53 Independent G1 Arrest Induced by dl-α-Difluoromethylornithine☆

Ornithine decarboxylase (ODC), which catalyzes polyamine biosynthesis, plays an essential role in cell growth. dl-α-Difluoromethylornithine (DFMO), a synthetic inhibitor of ODC, inhibits cell growth. However, the exact mechanism by which polyamine depletion by DFMO results in growth inhibition remains to be elucidated. We clarified the mechanisms by which DFMO inhibits human gastric cancer cell (MKN45) growth. DFMO induced MKN45 cell G1 phase arrest after 48 h, and the percentage of G1 arrest cells continued to increase until 72 h. Expression of p21 and phosphorylation of Stat1 were significantly induced by DFMO at 24 h. Luciferase assay and gel shift assay showed specific binding of Stat1 to the p21 promoter, and promoter activity was activated at 24 h. In dominant negative p53 expressing cells, DFMO significantly induced p21 expression, arrested cells at G1 phase, and suppressed cell growth effectively. These results suggest that DFMO induced MKN45 cell arrest at G1 phase in a p53 independent manner, and Stat1 is, at least in part, involved in G1 arrest.