OKADAIC ACID INHIBITS PDGF-INDUCED PROLIFERATION AND DECREASES PDGF RECEPTOR NUMBER IN C3H/10T1/2 MOUSE FIBROBLASTS

Okadaic acid is both a potent inhibitor of protein serine/threonine phosphatases and a tumor promoter in the mouse skin model. We have previously shown that at non-toxic nanomolar concentrations okadaic acid reversibly inhibits induction (promotion) by PDGF of transformed cells by the 'complete' and 'two-stage' protocols in the C3H/10T1/2 mouse fibroblast transformation assay. In the present study we have demonstrated that treatment of confluent and proliferatively quiescent C3H/10T1/2 mouse fibroblasts with low doses of okadaic acid inhibits the platelet-derived growth factor (PDGF)-induced mitogenic response. This inhibition is accompanied by a loss of PDGF binding sites, a decreased PDGF-induced phosphatidylinositol turnover and a decrease in the PDGF-induced intracellular calcium signal. The decrease in the PDGF-generated intracellular signalling processes represents a mechanism by which okadaic acid inhibits PDGF-induced proliferation and the promotion of in vitro neoplastic transformation by PDGF.