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

• Published in: The Journal of biological chemistry 1993-10, Vol.268 (30), p.22227-22230
• Main Authors: McGuire, T.F., Corey, S.J., Sebti, S.M.
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Adenosine Triphosphate - metabolism; Animals; Biological and medical sciences; Cell physiology; Fibroblasts - drug effects; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Insulin - pharmacology; Kinetics; Lovastatin - pharmacology; Macromolecular Substances; Mice; Molecular and cellular biology; Phosphatidylinositol 3-Kinases; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Phosphotyrosine; Platelet-Derived Growth Factor - antagonists & inhibitors; Platelet-Derived Growth Factor - pharmacology; Protein Binding; Receptors, Platelet-Derived Growth Factor - metabolism; Signal transduction; Tyrosine - analogs & derivatives; Tyrosine - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(18)41512-8

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.