INHIBITION OF CELL-GROWTH OF HUMAN HEPATOMA-CELL LINE (HEP G2) BY A FARNESYL-PROTEIN TRANSFERASE INHIBITOR - A PREFERENTIAL SUPPRESSION OF RAS FARNESYLATION

So far, treatment with anti-cancer agents has failed to achieve satisf actory results in hepatocellular carcinoma. In the process of hepatoca rcinogenesis, ras has been shown to play a role. ras requires a farnes yl moiety for activation. It has been found that UCFI-C (manumycin), a n antibiotic, inhibits farnesyl protein transferase, an enzyme that ca talyzes farnesylation. Therefore, we investigated the effects of UCFI- C on cell growth, prenylation of cellular proteins including ras and R ap I, MAP kinase activity, activities of 3-hydroxy-3-methylglutaryl-co enzyme A reductase, and synthesis of cholesterol in a ras-activated hu man hepatoma cell line, Hep G2. Treatment with varying concentrations of UCFI-C (10-30 mu M) for 24 and 72 hr resulted in a time- and dose-d ependent inhibition of cell numbers. H-3-Thymidine incorporation was a lso inhibited in a dose-dependent manner, with 50% inhibition after 44 hr being observed at a concentration of 17 mu M. UCFI-C dose-dependen tly inhibited ras farnesylation and MAP kinase activity, but did not d ecrease Rap I geranylgeranylation or prenylation of 21- to 26-kDa prot eins. Neither the activities of 3-hydroxy-3-methylglutaryl-coenzyme A reductase nor cholesterol synthesis were inhibited. These results sugg est that UCFI-C antagonizes the growth of Hep G2 via the suppression o f ras farnesylation and could be a lead for the development of new ant i-cancer agents blocking the function of oncogenic ras associated with human cancer, including hepatocellular carcinoma. (C) 1996 Wiley-Liss , Inc.