In vitro activation of mouse skin protein kinase C by fatty acids and their hydroxylated metabolites.
To understand how dietary fatty acids differentially modulate mouse skin tumorigenesis, the ability of specific fatty acids and their derivatives to activate murine epidermal protein kinase C (PKC) in vitro was investigated. Total PKC from untreated female SSIN mouse skin was partially purified and incubated with specific fatty acids at concentrations up to 300 microM in the presence of Ca2+ and phosphatidylserine. The cis-unsaturated fatty acids tested, ranging from 16:1 to 22:6, stimulated PKC activity in a similar dose-dependent manner with an approximate threefold maximum increase over control. Neither the number of cis-double bonds nor the chainlength of these fatty acids affected their relative ability to activate PKC. trans-Fatty acids, with the exception of linoelaidic acid (t,t-18:2n-6), exhibited about half of the potency of their corresponding cis-isomers in stimulating PKC at the plateau concentration (200 microM) or lower. Substitutions close to the double bond on cis-fatty acids abolished their ability to activate PKC. The hydroxylated metabolites of arachidonic acid (20:4n-6) and linoleic acid (c,c-18:2n-6), i.e., the hydroxyeicosatetraenoic acids (HETE) and hydroxyoctadecadienoic acids (HODE), also activated mouse skin PKC in vitro, but only about half as effectively as did the respective parent fatty acids. The results suggest that both hydroxyl substitution and trans-configuration of HETE and HODE are responsible for their reduced ability to activate PKC. Overall the data suggests that the reduced skin tumor yield observed in mice fed diets high in c,c-18:2n-6 is not likely to be due to differences in the ability of c,c-18:2n-6 or 20:4n-6, or their metabolites, to activate PKC.
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University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville 78957.
Bartek
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Fischer
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D000818:Animals; D004041:Dietary Fats / Q000494:pharmacology*; D004789:Enzyme Activation; D004817:Epidermis / Q000187:drug effects* / Q000201:enzymology; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006900:Hydroxylation; D066298:In Vitro Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D011493:Protein Kinase C / Q000378:metabolism*; D012878:Skin Neoplasms / Q000201:enzymology*
D004041:Dietary Fats; D005227:Fatty Acids; D011493:Protein Kinase C