Lovastatin induces apoptosis of spontaneously immortalized rat brain neuroblasts: Involvement of nonsterol isoprenoid biosynthesis inhibition

We have examined the effects of lovastatin and pravastatin (competitive HMG -CoA reductase inhibitors) on the growth and survival of rat brain neurobla sts. Lovastatin, but not pravastatin, suppressed cell growth by inducing ap optosis of neuroblasts in a dose- and time-dependent manner. Apoptosis was accompanied by a decrease in both Bcl-2 and Bcl-xL protein levels, suggesti ng that changes in the expression of these genes may contribute to apoptosi s following lovastatin treatment. Lovastatin treatment was also associated with decreased prenylation of both Ras and Rho A proteins whereas Rac 1 ger anylgeranylation was not affected. Lovastatin effects were fully prevented by mevalonate. The present data suggest that lovastatin induces apoptosis o f rat brain neuroblasts by its capacity to decrease the prenylation of spec ific proteins involved in signal transduction pathways that control growth and survival of neuronal cells.