Vitamin K3 preferentially inhibits stimulation of phospholipase D-mediated hydrolysis of phosphatidylethanolamine by protein kinase C activators in NIH 3T3 fibroblasts.
Vitamin K3 (menadione), a synthetic vitamin K congener, inhibits the growth of tumor cells. Here, we examined possible effects of vitamin K3 on phospholipase D (PLD) activity, an enzyme which produces growth regulatory substances. In NIH 3T3 fibroblasts, vitamin K3 (50-100 microM) alone had no effect on PLD-catalyzed formation of phosphatidylethanol, a marker of PLD activity, but it slightly (10-21%) inhibited the stimulatory effect of phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC). Of the two major substrates of PLD, phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn), vitamin K3 (10-100 microM) preferentially inhibited PtdEtn hydrolysis when stimulated by PMA or platelet-derived growth factor, the latter being a hormonal activator of PKC. Vitamin K3 had no inhibitory effect on sphingosine- or staurosporine-induced hydrolysis of PtdEtn or PtdCho. Inhibition of PMA-induced PtdEtn hydrolysis by vitamin K3 was effectively reduced by both cysteine (1 mM) and reduced glutathione (1 mM) and was mimicked by the superoxide-generating xanthine/xanthine oxidase system. The results show that vitamin K3 preferentially inhibits the effects of PKC activators on PLD-mediated hydrolysis of PtdEtn by a mechanism which may involve oxidation of thiols in a critically important regulatory component.
Tomono
M
M
Hormel Institute, University of Minnesota, Austin 55912.
Kiss
Z
Z
D016475:3T3 Cells; D000818:Animals; D003545:Cysteine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology; D006868:Hydrolysis; D051379:Mice; D010714:Phosphatidylethanolamines / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014812:Vitamin K / Q000494:pharmacology*; D019820:Xanthine; D014969:Xanthine Oxidase / Q000378:metabolism; D014970:Xanthines / Q000378:metabolism
D010714:Phosphatidylethanolamines; D010982:Platelet-Derived Growth Factor; D014970:Xanthines; D013481:Superoxides; D014812:Vitamin K; D019820:Xanthine; D014969:Xanthine Oxidase; D011493:Protein Kinase C; D010739:Phospholipase D; D005978:Glutathione; D003545:Cysteine; D013755:Tetradecanoylphorbol Acetate