STRUCTURE-ACTIVITY RELATIONSHIP FOR POTENTIATION OF EGF-DEPENDENT MITOGENESIS BY OXYGENATED METABOLITES OF LINOLEIC-ACID

Epidermal growth factor induces the oxygenation of linoleic acid in Sy rian hamster embryo fibroblasts, and the lipoxygenase-derived products potentiate the mitogenic signal. We have further characterized the li noleate metabolites of growth factor-activated cells by chiral phase H PLC analysis. The primary product was identified as the pure (S) enant iomer of 13-hydroxyoctadecadienoic acid (HODE). In comparison to 13(R) -HODE isomer, only the biologically derived 13(S)-HODE was active in a ugmenting DNA synthesis as assessed by [H-3]thymidine incorporation. T o extend these investigations, we defined the structural requirements of analogous lipid compounds necessary for stimulation of mitogenesis in these cells. Carbon-chain length, degree of unsaturation, type of o xidized functionality, position of oxygenated moiety, double-bond geom etry, and chirality were all identified as factors that modulate the m itogenic activity of related compounds. The results demonstrate a high degree of specificity for (S)-isomer hydro(pero)xylinoleic acid metab olites in stimulating DNA synthesis and further define the relationshi p between linoleic acid metabolism and growth-factor-dependent cell gr owth. (C) 1994 Academic Press, Inc.