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

✍ Scribed by Toshihiko Nagase; Sumio Kawata; Shinji Tamura; Yukihiko Matsuda; Yoshiaki Inui; Eiji Yamasaki; Hiroshi Ishiguro; Toshio Ito; Yuji Matsuzawa

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: French
• Weight: 776 KB
• Volume: 65
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(19960301)65:5<620::aid-ijc11>3.0.co;2-b

✦ Synopsis

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 UCF I -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-methylglutarylcoenzyme A reductase, and synthesis of cholesterol in a rasactivated human hepatoma cell line, Hep G2. Treatment with varying concentrations of UCF I -C (I 0-30 pM) for 24 and 72 hr resulted in a time-and dose-dependent inhibition of cell numbers. 3HH-Thymidine incorporation was also inhibited in a dose-dependent manner, with 50% inhibition after 44 hr being observed at a concentration of 17 pM. UCFI-C dose-dependently inhibited ras famesylation and MAP kinase activity, but did not decrease Rap I geranylgeranylation or prenylation of 2 Ito 26-kDa proteins. Neither the activities of 3-hydroxy-3methylglutaryl-coenzyme A reductase nor cholesterol synthesis were inhibited. These results suggest that UCF I -C antagonizes