GROWTH-INHIBITION OF RAT-LIVER EPITHELIAL TUMOR-CELLS BY MONOTERPENESDOES NOT INVOLVE RAS PLASMA-MEMBRANE ASSOCIATION

The role of altered ras oncoprotein (Ras) farnesylation and membrane a ssociation in the growth inhibitory effects of several monoterpenes (l imonene, perillic acid, perillyl alcohol, menthol, pinene and cineole) was investigated in rat liver epithelial cells. Ad of the above compo unds except cineole inhibited the growth of viral Ha-ras-transformed r at liver epithelial cells (WB-ras cells) at concentrations of 0.25-2.5 mM. These cells, however, were not necessarily more sensitive to thes e compounds compared to non-transformed and viral raf-transformed rat liver epithelial cells. Growth inhibition by limonene, perillic acid a nd pinene was only partially restored (20-50%) by supplementing the cu lture medium with 2 mM mevalonic acid. Western blot analyses of cytoso lic. and membranous fractions of WB-ras cells treated with monoterpene s indicated no change in Ras distribution. In contrast, lovastatin, a potent inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase a nd Ras farnesylation, specifically reduced WB-ras cell growth and incr eased cytosolic levels of Ras. Thus, monoterpene-induced growth inhibi tion of rat liver epithelial cells was dissimilar to lovastatin and di d not apear to involve altered Ras plasma membrane association.