Reversal of ras-induced inhibition of gap-junctional intercellular communication, transformation, and tumorigenesis by lovastatin.
The plasma-membrane association and transforming activity of the ras oncoprotein p21 are dependent upon posttranslational farnesylation. Farnesyl synthesis and p21 ras farnesylation are inhibited by hydroxymethylglutaryl-CoA reductase inhibitors such as lovastatin. In this study, we examined whether lovastatin could reverse the transformed phenotype of a v-Ha-ras-transformed rat liver epithelial cell line (WB-ras cells) and if changes were associated with the enhancement of gap-junctional intercellular communication (GJIC). WB-ras cells grow in soft agar, have reduced GJIC, and are highly tumorigenic. Membrane association of p21 ras in these cells was inhibited after in vitro treatment with lovastatin (0.1-0.5 microM) for 48 h. Concomitantly, the cells displayed a more normal morphology, decreased growth in soft agar, and enhanced GJIC. These changes were prevented by cotreatment with mevalonic acid. The morphology and GJIC of rat liver epithelial cells transformed with other oncogenes (src, neu, and raf/myc) were not affected by lovastatin. Intrahepatic WB-ras tumors were induced in male rats by intraportal-vein injection of WB-ras cells. The size and DNA labeling index of these tumors were decreased approximately 75% by administration of lovastatin (5 mg/kg orally twice daily for 2 wk). These results suggest that lovastatin reversed the transformed phenotype of WB-ras cells by inhibiting p21 ras plasma membrane association. Furthermore, the concomitant enhancement of GJIC in lovastatin-treated cells suggests a role for reduced GJIC in the expression of the transformed phenotype.
Ruch
R J
RJ
Department of Pathology, Medical College of Ohio, Toledo 43699.
Madhukar
B V
BV
Trosko
J E
JE
Klaunig
J E
JE
D000818:Animals; D002450:Cell Communication / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D004347:Drug Interactions; D004847:Epithelial Cells; D011905:Genes, ras / Q000187:drug effects / Q000502:physiology*; D007365:Intercellular Junctions / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D008099:Liver / Q000166:cytology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008148:Lovastatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D008148:Lovastatin; D016283:Proto-Oncogene Proteins p21(ras); D008798:Mevalonic Acid