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12(S)-hydroxyeicosatetraenoic acid regulates DNA synthesis and protooncogene expression induced by epidermal growth factor and insulin in rat lens epithelium.

Neonatal rat lens epithelium has a high 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] synthetic capacity, which decreases as epithelial cell proliferation decreases with age. To determine whether products of the 12-lipoxygenase pathway are involved in lens cell proliferation, we measured the effect of 12-lipoxygenase inhibitors on endogenous 12-HETE production, epidermal growth factor/insulin-stimulated DNA synthesis and protooncogene expression in cultured neonatal rat lens epithelial cells. Incubation of neonatal rat lenses in epidermal growth factor plus insulin, which stimulated endogenous 12-HETE production 8- to 10-fold, also produced a transient induction of c-fos and c-myc mRNAs after 2 to 3 h, followed by a round of DNA synthesis approximately 20 h later. The lipoxygenase inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate, strongly inhibited both the endogenous 12-HETE synthesis and growth factor-stimulated DNA synthesis with a half-maximal inhibition between 10 and 20 microM. Cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (10 microM) also inhibited the expression of c-fos and c-myc mRNA and, to a lesser extent, c-jun mRNA. The inhibitory effects of cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate on protooncogene expression and DNA synthesis were prevented by 0.3 microM 12(S)-HETE but not by equivalent concentrations of either 5(S)-HETE or 15(S)-HETE. These findings suggest that endogenously synthesized 12(S)-HETE may mediate epidermal growth factor/insulin-stimulated DNA synthesis in neonatal rat lens epithelial cells by regulating protooncogene expression.