Phosphatidylinositol 3-kinase is required for the induction of ornithine decarboxylase in leukemia cells stimulated to growth

The involvement of phosphatidylinositol 3-kinase (PI3K) in the induction of ornithine decarboxylase (ODC) was investigated by using specific PI3K inhibitors. In difluoromethylornithine-resistant L1210 cells stimulated to growth from quiescence, treatment with LY294002 inhibited cell growth and provoked a complete block of the induction of ODC activity (IC50 similar to 2 mu M) and ODC protein. Some reduction in the accumulation of ODC mRNA was also observed, whereas ODC turnover was not affected significantly. Wortmannin, another specific inhibitor of PI3K, structurally unrelated to LY294002, also inhibited ODC induction with an IC50 of about 10 nM. These results indicate that PI3K activity is required for the induction of ODC, possibly affecting both ODC mRNA level and translation, Since p70 S6 kinase (p70(S6K)) is considered an important mediator of PI3K action in several experimental systems, the effect of rapamycin, which can lead to selective inhibition of p70(S6K), was also investigated. Rapamycin inhibited p70(S6K) activity and produced ODC inhibiting effects similar to those elicited by LY294002, However, LY294002 and wortmannin at concentrations which inhibited almost completely PI3K activity did not decrease p70(S6K) activity, suggesting that p70(S6K) does not mediate the PI3K effects on ODC, but may lie on a separate pathway in this experimental model. (C) 1997 Academic Press.