REGULATION OF CELL GROWTH BY LINOLEIC ACID METABOLITES IN SHE CELLS

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Summary of Work: We have used Syrian hamster embryo cells (SHE) to study the modulation of cell growth and apoptosis by lipid metabolites. EGF-dependent mitogenesis was inhibited by lipoxygenase inhibitors, but not attenuated by PGHS inhibitors. EGF did not stimulate prostaglandin formation, but did stimulate the metabolism of linoleic acid to 13(S)-HODE. The formation of 13-HODE is regulated by the tyrosine kinase activity of the EGF receptor, but the mechanism is poorly understood. The linoleic acid metabolite potentiated EGF-dependent mitogenesis in the supB+ SHE cells, but this response was lost on progression to the supB-. Structure-activity investigations revealed that 13(S)-HpODE was the most effective lipid compound in stimulating EGF-regulated DNA synthesis in SHE cells. This suggested a specific site for 13(S)-HpODE effects. Since the formation of 13(S)-HpODE up-regulates EGF-dependent cell growth, we prepared stable transfectants of supB+ cells that over-express 15-LO. This increased expression of 15-lipoxygenase and formation of 13 (S)-HpODE increases the rate of cell growth 4 fold. These findings provide additional evidence for lipid metabolites as regulators of cell proliferation.