ARACHIDONATE HAS PROTUMOR-PROMOTING ACTION THAT IS INHIBITED BY LINOLEATE IN MOUSE SKIN CARCINOGENESIS

Previous studies demonstrated a requirement for arachidonic acid metab olites in tumor development in mouse skin. The goal of this study was to determine whether the arachidonate content of epidermal phospholipi ds could be altered by increasing dietary levels of linoleate and whet her specific metabolites of linoleate and arachidonate have dissimilar biological effects. In a series of tumor studies In which the quantit y of dietary linoleate was incrementally increased, a slight reduction in phospholipid levels of arachidonate was observed that correlated w ith an increased phospholipid level of linoleate and a suppression in tumor yield. A comparison of the arachidonate lipoxygenase metabolite 12-hydroxyeicosatetraenoic acid (12-HETE) with the 13-hydroxyoctadecad ienoic acid (13-HODE) lipoxygenase metabolite of linoleate revealed th at 12-HETE has biological activities that mimic the phorbol ester tumo r promoters, whereas 13-HODE has antithetical effects. Specifically, 1 2(S)-HETE enhanced the activation of protein kinase C by phorbol ester s, mimicked phorbol ester-induced adhesion of keratinocytes to fibrone ctin and mimicked phorbol ester repression of expression of a differen tiation-related gene, keratin-1. 13-HODE blocked 12-HETE-induced cell adhesion and prevented 12-HETE-induced suppression of keratin-1 expres sion. Overall, these studies suggest that arachidonate and linoleate h ave opposing functions in the epidermis, particularly with regard to e vents involved in tumor development.