Effects of prostaglandins and hydroxyoctadecadienoic acid on epidermal growth factor-dependent DNA synthesis and c-myc proto-oncogene expression in Syrian hamster embryo cells

Abstract

Epidermal growth factor (EGF) stimulates DNA synthesis in quiescent Syrian hamster embryo (SHE) cells. Work in the present authors' laboratory has shown that the formation of 9- and 13-hydroxyoctadecadienoic acid (HODEs), 15-lipoxygenase-derived metabolites of linoleic acid, are involved in the mitogenic response to EGF in these cells (Glasgow et al. (1992) J. Biol. Chem. 267, 10771-10779). SHE cells also produce prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha). We now report the effects of HODEs and prostaglandins on EGF-dependent expression of the growth-related proto-oncogene c-myc in SHE cells. Treatment of cells with eicosatetraynoic acid (ETYA), which blocks EGF-dependent HODE formation, inhibited the mitogenic response to EGF, while exogenous 13-HODE potentiated EGF-dependent DNA synthesis. However, neither ETYA or 13-HODE altered the accumulation of c-myc mRNA in response to EGF. In contrast, PGE2 inhibited EGF-induced DNA synthesis and down-regulated EGF-stimulated c-myc mRNA accumulation in a dose-dependent manner, whereas PGF2 alpha had no effect on these responses. PGE2, but not PGF2 alpha, induced a rapid increase in cAMP formation, and both forskolin and 8-(4-chlorophenylthio)-cAMP mimicked the inhibitory effects of PGE2 on EGF-dependent DNA synthesis and c-myc mRNA accumulation, suggesting that the involvement of cAMP. The results indicate that the modulation of EGF-dependent DNA synthesis by PGE2, but not by HODEs, is associated with altered expression of the proto-oncogene c-myc in SHE cells.