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 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 Rapl, 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 UCF1-C(10-30 microM 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 microM. UCFI-C dose-dependently inhibited ras farnesylation and MAP kinase activity, but did not decrease Rap 1++ 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.
Nagase
T
T
Second Department of Internal Medicine, Osaka University Medical School, Japan.
Kawata
S
S
Tamura
S
S
Matsuda
Y
Y
Inui
Y
Y
Yamasaki
E
E
Ishiguro
H
H
Ito
T
T
Matsuzawa
Y
Y
D019883:Alkyl and Aryl Transferases; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D011090:Polyenes / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides; D014166:Transferases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D020668:rap GTP-Binding Proteins
D011090:Polyenes; D053284:Polyunsaturated Alkamides; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D020668:rap GTP-Binding Proteins; C054474:manumycin