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.
McGuire
T F
TF
University of Pittsburgh, School of Medicine, Department of Pharmacology, Pennsylvania.
Corey
S J
SJ
Sebti
S M
SM
D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D008148:Lovastatin / Q000494:pharmacology*; D046911:Macromolecular Substances; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D019000:Phosphotyrosine; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011485:Protein Binding; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D007328:Insulin; D046911:Macromolecular Substances; D010982:Platelet-Derived Growth Factor; D019000:Phosphotyrosine; D014443:Tyrosine; D000255:Adenosine Triphosphate; D008148:Lovastatin; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017479:Receptors, Platelet-Derived Growth Factor