CELLULAR PROLIFERATION AND LIPID-METABOLISM - IMPORTANCE OF LIPOXYGENASES IN MODULATING EPIDERMAL GROWTH FACTOR-DEPENDENT MITOGENESIS

In this article we have reviewed and discussed the results of our inve stigation of lipid metabolites as modulators of epidermal growth facto r (EGF) signaling pathways. We have studied epidermal growth factor-de pendent mitogenesis in BALB/c 3T3 and Syrian hamster embryo (SHE) cell s in culture. We observed that EGF stimulates the formation of prostag landins in BALB/c 3T3 cells and their formation appears to be necessar y for EGF dependent mitogenesis. EGF did not stimulate PGE, formation in SHE cells and in fact, exogenously added PGE, inhibited mitogenesis . fn both cell lines, EGF stimulated the formation of lipoxygenase-der ived 13(S)-hydroxyoctadecadienoic acid (13-HODE) and inhibition of 13- HODE formation attenuated mitogenesis. The addition of 13-(S)-HODE enh anced EGF-dependent mitogenesis but when added alone, the compound was not mitogenic. Other metabolites, including lipoxygenase metabolites of arachidonic acid, were either weak simulators of EGF-dependent mito genesis or essentially inactive. The 13(S)-HODE appears to be formed b y an apparently unique lipoxygenase that is regulated by the tyrosine kinase activity of the EGF receptor. The mechanisms by which lipids, p articularly the lipoxygenase-derived linoleic acid metabolites, modula te the EGF signaling pathways leading to cell proliferation is discuss ed. The possible significance of lipoxygenase and prostaglandin H synt hase-dependent metabolism of unsaturated fatty acids in breast and col on cancer is also discussed.