Modulation of phorbol ester-associated events in epidermal cells by linoleate and arachidonate

To elucidate the events elicited by the skin tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA), which are modulated by linoleic acid (LA) and arachidonic acid (AA), the activity of these fatty acids in cultured mouse epidermal cells was compared. Approximately 94% of either exogenous radiolabelled fatty acid was incorporated into the total phospholipid pool over 15 h. The relative distribution among the phospholipid classes differed, however, such that approximately 70% of phospholipid-associated ¹⁴C]-LA was found in phosphatidylcholine, compared to approximately 30% for ¹⁴C]AA. Phosphatidylethanolamine and phosphatidylinositol/phosphatidylserine contained 17 and 13% of the phospholipid ¹⁴C]LA, and 34 and 30% of ¹⁴C]AA, respectively. Prostaglandin (PG) E₂ production was low but similar in unstimulated cultures prelabelled with either ¹⁴C]LA or ¹⁴C]AA. However, in cultures treated with TPA (1.6 μM), ¹⁴C]AA-prelabelling resulted in approximately three times the amount of ¹⁴C]PGE₂ compared with cultures prelabelled with ¹⁴C]LA. Cultured cells were found to contain significant δ6 desaturase activity, which may enable conversion of LA to AA, and thus may account for the observed PGE₂ production from ¹⁴C]LA treated cells. AA-Supplemented (1.6 μM) cultures supported approximately twice the induction of ornithine decarboxylase activity by TPA compared with cultures treated with 1.8 μM LA. Activation of partially purified protein kinase C was similar for either fatty acid tested over a 10–300 μM dose range. Overall, the results suggest that LA does not have the same biological activity as AA with regard to several TPA-associated events known to be important in skin tumor promotion. This reduced biological activity of LA may be partly responsible for the known inhibition of mouse skin tumor promotion by high dietary levels of LA Leyton, J., Lee, M.L., Locniskar, M.F., Belury, M.A., Slaga, T.J., Bechtel, D., and Fischer, S.M. (1991)Cancer Res. 51, 907–915].