Journal of Lipid Research, Vol 38, 49-60, Copyright © 1997 by Lipid Research, Inc.

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Epidermal growth factor-stimulated production of esterified 13(S)- hydroxyoctadecadienoic acid is associated with tumor suppressor phenotype in Syrian hamster embryo fibroblasts

R Hui, AL Everhart and WC Glasgow
Laboratory of Molecular Biophysics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.

Epidermal growth factor (EGF) stimulates the lipoxygenase metabolism of linoleic acid to 13(S)-hydroxyoctadecadienoic acid (HODE) in Syrian hamster embryo (SHE) fibroblasts. 13(S)-HODE is a potent and specific enhancer of EGF-dependent DNA synthesis in normal phenotypic SHE cells (supB+), but is inactive in variant SHE cells that have lost tumor suppressor gene function (supB-). EGF activation of quiescent SHE cells results in increased levels of 13-HODE esterified in cellular phospholipid and triglyceride. Steric analyses suggest that this metabolite is generated in part by direct oxygenation of membrane lipids by an n-6 lipoxygenase. In studies on the uptake and mobilization of 13-HODE in SHE cells, we observed EGF to stimulate a time- and dose-dependent incorporation and reacylation of the mono- hydroxy linoleate metabolite. The level of 13-HODE uptake in supB+ cells is twice that of supB-. Among classes of phospholipids, radiolabeled 13-HODE is esterified predominantly into phosphatidylcholine and this distribution pattern is similar for both SHE cell lines. Pretreatment of cells with the tyrosine kinase inhibitor methyl-2,5-dihydroxycinnamate blocks EGF-stimulated HODE incorporation. Inhibition of tyrosine phosphatase activity with vanadate potentiates HODE uptake in supB+ but not supB- cells. Moreover, activation of protein kinase C with phorbol ester stimulates HODE incorporation in the supB+ line only. The differential effects of EGF on 13-HODE uptake and mobilization in supB+ and supB- cells appear to be related to loss of the tumor suppressor phenotype. EGF-stimulated generation of esterified 13-HODE may be an important biological process in determining the mechanism and site of HODE interaction with the mitogenic signaling pathway.
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