The growth inhibitory effects of vitamins K and their actions on gene expression.
A characteristic defect occurs in rat and human hepatocellular carcinoma (HCC) resulting in a loss of function of the vitamin K-dependent enzyme gamma-glutamyl-carboxylase in the tumor but not in the underlying liver. This causes the secretion of elevated levels of the immature or des-gamma-carboxylated form of prothrombin, which is used as a marker of HCC. We investigated whether, using the defined conditions of growing HCC cell lines in tissue culture, addition of the naturally occurring vitamins K1 or K2 or the synthetic vitamin K3 could influence the secretion of immature prothrombin. We found that vitamins K1, K2 and K3 all suppressed the secretion of immature prothrombin into the tissue culture medium. Vitamins K2 and K3 were also found to inhibit growth of the HCC cell line, in an apparently nontoxic and reversible manner. The influence of the vitamins K on the expression of some genes related to vitamin K action was examined and compared with that of another growth inhibitor, TGF beta 1 protein. The vitamins K were found to increase the expression of prothrombin and carboxylase messenger RNA and c-myc messenger RNA, but had no effects on the expression of TGF beta 1 messenger RNA. By contrast, TGF beta 1 increased TGF beta 1 messenger RNA levels, but had no effects on the other genes, suggesting a different pathway. The previously studied vitamin K3-mediated inhibition of growth was antagonized by the addition of catalase to the culture medium, but the inhibitory effects of vitamin K2 were not antagonized.(ABSTRACT TRUNCATED AT 250 WORDS)
Wang
Z
Z
Pittsburgh Transplant Institute, University of Pittsburgh School of Medicine, PA, USA.
Wang
M
M
Finn
F
F
Carr
B I
BI
D015415:Biomarkers; D014408:Biomarkers, Tumor / Q000378:metabolism; D019735:Carbon-Carbon Ligases; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D016259:Genes, myc / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008025:Ligases / Q000235:genetics; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D011498:Protein Precursors; D011516:Prothrombin / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014812:Vitamin K / Q000494:pharmacology*
D015415:Biomarkers; D014408:Biomarkers, Tumor; D006131:Growth Inhibitors; D011498:Protein Precursors; D016212:Transforming Growth Factor beta; D014812:Vitamin K; C008208:acarboxyprothrombin; D011516:Prothrombin; D008025:Ligases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase