MODULATION OF PHORBOL ESTER-ASSOCIATED EVENTS IN EPIDERMAL-CELLS BY LINOLEATE AND ARACHIDONATE

To elucidate the events elicited by the skin tumor promoter 12-O-tetra decanoylphorbol-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 eith er exogenous radiolabelled fatty acid was incorporated into the total phospholipid pool over 15 h. The relative distribution among the phosp holipid classes differed, however, such that approximately 70% of phos pholipid-associated [C-14]LA was found in phosphatidylcholine, compare d to approximately 30% for [C-14]AA. Phosphatidylethanolamine and phos phatidylinositol/phosphatidylserine contained 17 and 13% of the phosph olipid [C-14]LA, and 34 and 30% of [C-14]AA, respectively. Prostagland in (PG) E2 production was low but similar in unstimulated cultures pre labelled with either [C-14]LA or [C-14]AA. However, in cultures treate d with TPA (1.6 muM), [C-14]AA-prelabelling resulted in approximately three times the amount of [C-14]PGE2 compared with cultures prelabelle d with [C-14]LA. Cultured cells were found to contain significant DELT A6 desaturase activity, which may enable conversion of LA to AA, and t hus may account for the observed PGE2 production from [C-14]LA treated cells. AA-Supplemented (1.6 muM) cultures supported approximately twi ce the induction of ornithine decarboxylase activity by TPA compared w ith cultures treated with 1.8 muM LA. Activation of partially purified protein kinase C was similar for either fatty acid tested over a 10-3 00 muM dose range. Overall, the results suggest that LA does not have the same biological activity as AA with regard to several TPA-associat ed events known to be important in skin tumor promotion. This reduced biological activity of LA may be partly responsible for the known inhi bition of mouse skin tumor promotion by high dietary levels of IA [Ley ton, J., Lee, M.L., Locniskar, M.F., Belury, MA., Slaga, T.J., Bechtel , D., and Fischer, S.M. (1991) Cancer Res. 51, 907-9151.