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Arachidonate Has Protumor-Promoting Action that is Inhibited by Linoleate in Mouse Skin Carcinogenesis^1,2,

Susan M. Fischer^*,3, Ruth A. Hagerman, Evelyn Li-Stiles^*, Herng-Hsiang Lo^*, Regina E. Maldve^*, Martha A. Belury and Mary F. Locniskar

The^* University of Texas M.D. Anderson Cancer Center, Science Park - Research Division, Smithville, TX 78759 The University of Texas at Austin, Division of Nutritional Sciences, Austin, TX 78712 Department of Food and Nutrition, Purdue University, West Lafayette, IN 47907

Previous studies demonstrated a requirement for arachidonic acid metabolites in tumor development in mouse skin. The goal of this study was to determine whether the arachidonate content of epidermal phospholipids could be altered by increasing dietary levels of linoleate and whether specific metabolites of linoleate and arachidonate have dissimilar biological effects. In a series of tumor studies in which the quantity of dietary linoleate was incrementally increased, a slight reduction in phospholipid levels of arachidonate was observed that correlated with 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-hydroxyoctadecadienoic acid (13-HODE) lipoxygenase metabolite of linoleate revealed that 12-HETE has biological activities that mimic the phorbol ester tumor promoters, whereas 13-HODE has antithetical effects. Specifically, 12(S)-HETE enhanced the activation of protein kinase C by phorbol esters, mimicked phorbol ester-induced adhesion of keratinocytes to fibronectin and mimicked phorbol ester repression of expression of a differentiation-related gene, keratin-1. 13-HODE blocked 12-HETE-induced cell adhesion and prevented 12-HETE-induced suppression of keratin-1 expression. Overall, these studies suggest that arachidonate and linoleate have opposing functions in the epidermis, particularly with regard to events involved in tumor development.

KEY WORDS: • arachidonate • linoleate • tumor promotion • mouse • lipoxygenase

¹ Presented as part of the symposium "Biological Effects of Dietary Arachidonic Acid" given at the Experimental Biology '95 meeting, Atlanta, GA, on April 11, 1995. This symposium was sponsored by the American Institute of Nutrition and was supported by a grant from the Cayman Chemical Company. Guest editors for the symposium were Jay Whelan, University of Tennessee, Knoxville, TN, and J. Bruce German, University of California, Davis, CA.

² Supported by grants CA-46886, CA-34443, CA-16672 from the National Cancer Institute and by the American Institute for Cancer Research.

³ To whom correspondence should be addressed: The University of Texas M.D. Anderson Cancer Center, Science Park, P. O. Box 389, Smithville, TX 78759.