Investigations are concerned with the oxidation of arachidonic and linoleic acid acids to prostaglandins (PG), leukotrienes and hydroxy-fatty acids and the relationship of this metabolism to the regulation or modulation of biological processes. We have studied the role of arachidonic and linoleic acids metabolism in the response of cells to growth factors. PGs are potent inhibitors of EGF-stimulated DNA synthesis ii Syrian hamster embryo (SHE) cells. The expression of c-myc is reduced in the presence of PG and appears not to be modulated in SHE cells by 13-HODE. In response to EGF both the BALBc cells and SHE cells metabolize linoleic acid to 9/13-hydroxyoctadecadienoic acid (9/13-HODE), 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-HODE significantly stimulated EGF dependent mitogenesis at concentration as low as 10E-10 M. EGF is required for the lipoxygenase to oxidize linoleic acid to 9/13-HODE. The data indicates that the 15-lipoxygenase is not induced but appears to be activated by either by translocation from the cytosol to the nuclear membranes or tyrosine phosphorylation of the 15-LO to an active form in cells. We have also studied the regulation of PHS expression in cells. TPA and other growth factors in synthesis of new PHS by enhancing the expression of PHS m-RNA. Other data indicates that steroids inhibit the expression of PHS. These findings suggest a possible important role for arachidonic and linoleic acid metabolism in regulating cell growth.
