Evidence for phosphatidylinositol 3-kinase-Akt-p70S6K pathway activation and transduction of mitogenic signals by platelet-derived growth factor in meningioma cells

Object. The intracellular events transducing mitogenic signals from platelet-derived growth factor-beta (PDGFbeta) receptor tyrosine kinases are not precisely known. In this study the authors evaluated whether the phosphatidylinositol 3-kinase (PI3-K)-Akt-p70(S6K) pathway is expressed in meningiomas, regulates their growth, and transduces mitogenic signals of PDGF-BB. Methods. Nine meningioma tumors obtained in humans were evaluated using Western blot analysis for phosphorylated (activated) Akt and phosphorylated p70(S6K). Cells cultured from seven of these meningiomas were also screened using Western blot analysis for Akt and for phosphorylated Akt and p70(S6K). The authors also evaluated whether PDGF-BB stimulation of meningioma cells was associated with the phosphorylation of Akt and p70(S6K) known to activate these kinases. In addition, the effects of wortmannin, an inhibitor of PI3-K, on proliferation and activation of Akt and p70(S6K) in meningioma cells stimulated with PDGF-BB were evaluated. Western blots of lysates from meningiomas demonstrated phosphorylated Akt and p70(S6K). Treatment with PDGF-BB stimulated phosphorylation of Akt and p70(S6K) in each meningioma cell culture. Wortmannin (500 and 1000 nM) significantly decreased PDGF-BB stimulation of meningioma cells (p < 0.001) while it reduced Akt and p70(S6K) phosphorylation but not mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) phosphorylation. Conclusions. These findings indicate that Akt and p70(S6K) are constitutively expressed and activated in meningioma cells and that the PI3-K-Akt-p70(S6K) pathway may participate in transduction of mitogenic signals in meningiomas independent of the Raf-1-MEK-1-MAPK/ERK cascade.