Inhibition of cell growth of human hepatoma cell line (HepG2) by a farnesyl protein transferase inhibitor: A preferential suppression of ras farnesylation

Open Access
Publisher Website
Google Scholar
Abstract
So far, treatment with anti‐cancer agents has failed to achieve satisfactory results in hepatocellular carcinoma. In the process of hepatocarcinogenesis, ras has been shown to play a role, ras requires a farnesyl moiety for activation. It has been found that UCFI‐C (manumycin), an antibiotic, inhibits farnesyl protein transferase, an enzyme that catalyzes farnesylation. Therefore, we investigated the effects of UCFI‐C on cell growth, prenylation of cellular proteins including ras and Rap I, MAP kinase activity, activities of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase, and synthesis of cholesterol in a ras‐activated human hepatoma cell line, Hep G2. Treatment with varying concentrations of UCFI‐C (10–30 μM) for 24 and 72 hr resulted in a time· and dose‐dependent inhibition of cell numbers. 3H‐Thymidine incorporation was also inhibited in a dose‐dependent manner, with 50% inhibition after 44 hr being observed at a concentration of 17 μM. UCFI‐C dose‐dependently inhibited ras farnesylation and MAP kinase activity, but did not decrease Rap I geranylgeranylation or prenylation of 21‐ to 26‐kDa proteins. Neither the activities of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase nor cholesterol synthesis were inhibited. These results suggest that UCFI‐C antagonizes the growth of Hep G2 via the suppression of ras farnesylation and could be a lead for the development of new anti‐cancer agents blocking the function of oncogenic ras associated with human cancer, including hepatocellular carcinoma.