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 in hibitor, blocked PGE(2) production in human A431 and WISH cells and mu rine 3T3 cells in response to epidermal growth factor and platelet-der ived growth factor. Blockade of growth factor-induced PGE(2) productio n was dose-dependent (IC50 approximate to 7-8 mu M). Genistein also ab olished 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 les s [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 ves icle. The IC50 of genistein for inhibition of prostaglandin H,synthase specific activity extracted from A431 and WISH cells approximated tha t half-maximal inhibitory concentration in the whole cell assay. These data indicate that genistein may interfere with arachidonic acid meta bolism at several key points by a mechanism(s) that is independent of its inhibitory action on receptor tyrosine protein kinases. Taken toge ther, these results also suggest that caution should be exercised when drawing conclusions about the putative role of tyrosine kinases in si gnal transduction events using genistein as a pharmacological blocker.