Investigations are concerned with the oxidation of arachidonic acid to prostaglandins (PG), leukotrienes and hydroxy-fatty acids and the relationship of this metabolism to the regulation or modulation of biological processes. We have investigated the mechanism responsible for the inhibition of PHS by peroxidase for inhibition to occur. We have also studied the role of arachidonic acid metabolism in the response of cells to growth factors. For BALBc cells, PGs are required for EGF but not PDGF stimulated DNA synthesis. The addition of EGF stimulates PG formation and the expression of c-myc occurs after PG formation. Inhibition of PG formation inhibits the expression of c-myc while the addition of PG restores the c-myc. Thus in these cells c-myc expression appears to be modulated by PGs. In contrast PGs are potent inhibitors of EGF-stimulated DNA synthesis in Syrian hamster embryo (SHE) cells. In response to EGF both the BALBc cells and SHE cells metabolize linoleic acid to 9/13-- hydroxyoctadecadienoic acid (9/13-HODD), which when added to these cells enhances DNA synthesis. Inhibition of the 15-lipoxygenase, that catalyzes this oxidation, inhibits DNA synthesis. The addition of 9/13-S-HODD significantly stimulated EGF dependent mitogenesis at concentration as low as 10(-10) M. Moreover, EGF is required for the lipoxygenase to oxidize linoleic acid to 9/13-HODD which suggest that EGF induces or activates the lipoxygenase. The data indicate that EGF-stimulated DNA synthesis requires the linoleic acid metabolites and that growth factors either activate or induce the synthesis of the 15-lipoxygenase. Studies are currently underway to further investigate these problems. These findings suggest a possible important role for arachidonic and linoleic acid metabolism in regulating cell growth.
