Modulation of small G protein isoprenylation by anticancer monoterpenes in in situ mammary gland epithelial cells.

Monoterpenes have been shown to both prevent and treat mammary cancer in animal models and are currently in clinical testing in advanced cancer patients. In this study, we investigated a biochemical modulation associated with the antitumor activity of monoterpenes, the inhibition of protein isoprenylation in monoterpene chemoprevention target tissue, i.e. the in situ mammary gland epithelial cells. We first developed a new methodology that for the first time permitted the study of protein isoprenylation and other products in the mevalonate pathway in in situ mammary cells. Using this approach, we found that chronically feeding rats with an anticancer dose of perillyl alcohol resulted in a 22% inhibition of coenzyme Q synthesis and a 19% inhibition of small G protein isoprenylation in mammary gland epithelial cells in situ. The greatest inhibition of small G protein isoprenylation observed was the 28% inhibition of isoprenylation of RhoA by type I geranylgeranyl protein transferase (GGPTase). Given that some substrates of type I GGPTase, such as RhoA and Rac1, have transforming properties, the possibility that the inhibition of type I GGPTase will change the cellular location and functionality of these proteins and thus contribute to the chemoprevention activity of monoterpenes, is discussed.