Geranylgeraniol restores cell proliferation to lovastatin treated C6 glial cells

Since we have previously shown that farnesol (F-OH) and geranylgeraniol (GG-OH) can be utilized for protein isoprenylation, the ability of the free allylic isoprenols to overcome the lovastatin-induced block on rat C6 glial cell proliferation has been investigated. Lovastatin an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in mevalonate biosynthesis, inhibited the rate of cell growth in a concentration dependent manner. The addition of mevalonate and GG-OH to lovastatin treated cells was shown to overcome the drug induced inhibition of cell proliferation. This result indicates that geranylgeraniol is capable of providing the mevalonic acid-derived products necessary to support cell growth. These results suggest that isoprenols are converted to an "activated' form, possibly the corresponding allylic pyrophosphate intermediate by reactions that remain to be characterized, prior to being utilized for sterol biosynthesis and protein isoprenylation.