Lovastatin inhibits platelet-derived growth factor (PDGF) stimulation of phosphatidylinositol 3-kinase activity as well as association of p85 subunit to tyrosine-phosphorylated PDGF receptor.

Lovastatin inhibits mitogenesis in cultured cells and growth of tumors in vivo by unknown mechanism(s). Phosphatidylinositol 3-kinase (PI-3-kinase) is a putative second messenger-generating enzyme whose physical association with the platelet-derived growth factor receptor (PDGFR) has been demonstrated to be required for the mitogenic activity of PDGF in cultured fibroblasts. Here we examine the effect of lovastatin on PDGF- and insulin-stimulated PI-3-kinase activity. In quiescent NIH-3T3 cells, PDGF (25 ng/ml) and insulin (200 nM) stimulate PI-3-kinase activity 10- and 6-fold, respectively. However, overnight pretreatment of cells with 10 microM lovastatin inhibits this stimulation of PI-3-kinase activity by PDGF and insulin. Immunoprecipitation of the PI-3-kinase p85 subunit demonstrates a PDGF-dependent association of PI-3-kinase with the tyrosine-autophosphorylated PDGFR. However, upon exposure of cells to 10 microns lovastatin for 40 h, the level of autophosphorylated PDGFR associating with PI-3-kinase after PDGF stimulation decreases significantly (75% reduction). No change in the expression of the PI-3-kinase p85 subunit was observed after treatment of cells with lovastatin. These results demonstrate that lovastatin disrupts a major growth factor signaling pathway and that inhibition of PDGF-induced association of PI-3-kinase with PDGFR and subsequent inhibition of PI-3-kinase activity is one potential mechanism by which lovastatin inhibits cell growth.