Inhibition of cell growth by lovastatin is independent of ras function.

We have investigated the inhibition of cell growth by lovastatin (previously known as mevinolin), an antagonist of hydroxymethylglutaryl coenzyme A reductase which blocks the processing and membrane localization of ras proteins via inhibition of polyisoprenylation. A series of NIH 3T3 cells transformed by oncogenes with activities that are dependent or independent of isoprenylated ras were studied, including cells transformed by myristylated ras protein that is isoprenylation independent. Treatment with lovastatin at concentrations ranging from 5 to 15 microM for up to 96 h resulted in a time- and dose-dependent inhibition of cell growth in all lines tested. The inhibition ranged from 25 to 50% when cells were treated with 5 microM lovastatin for 48 h, to 72-90% for cells treated with 15 microM lovastatin for 96 h. Cells transformed by c-ras, v-ras, v-src, v-raf, and the myristylated ras genes displayed similar sensitivities; the parental NIH 3T3 line was the most resistant of the lines tested. Metabolic labeling of control and lovastatin-treated cells with [35S]methionine or tritiated lipids revealed that 15 microM lovastatin blocked the processing of both endogenous ras and v-ras proteins yet had no effect on the lipidation of myristylated ras proteins. Addition of 300 microM mevalonic acid overcame the inhibition induced by 15 microM lovastatin. Thus the inhibition of cell growth in vitro by lovastatin did not show specificity for cells the transformation of which is dependent upon isoprenylated ras protein. It is therefore likely that the inhibition of other pathways affected by lovastatin, such as cholesterol biosynthesis or the processing of other cellular proteins, are responsible for the growth inhibition by lovastatin.