Genistein suppresses EGF-induced prostaglandin biosynthesis by a mechanism independent of EGF receptor tyrosine kinase inhibition

This study demonstrated that genistein, a selective tyrosine kinase inhibitor, blocked PGE(2) production in human A431 and WISH cells and murine 3T3 cells in response to epidermal growth factor and platelet-derived growth factor. Blockade of growth factor-induced PGE(2) production was dose-dependent (IC50 approximate to 7-8 mu M). Genistein also abolished PGE(2) formation in response to calcium ionophores, A23187 and ionomycin, and the phorbol estes, phorbol myristate acetate. Moreover, genistein-treated A431 and WISH cells incorporated significantly less [H-3]arachidonic acid into membrane phospholipids than control cells. Finally, genistein decreased the specific activity of prostaglandin H-2 synthase prepared from A431 cells, WISH cells, and yam seminal vesicle. The IC50 of genistein for inhibition of prostaglandin H,synthase specific activity extracted from A431 and WISH cells approximated that half-maximal inhibitory concentration in the whole cell assay. These data indicate that genistein may interfere with arachidonic acid metabolism at several key points by a mechanism(s) that is independent of its inhibitory action on receptor tyrosine protein kinases. Taken together, these results also suggest that caution should be exercised when drawing conclusions about the putative role of tyrosine kinases in signal transduction events using genistein as a pharmacological blocker.