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 PGE2 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 PGE2 production was dose-dependent (IC50 approximately equal to 7-8 microM). Genistein also abolished PGE2 formation in response to calcium ionophores, A23187 and ionomycin, and the phorbol ester, phorbol myristate acetate. Moreover, genistein-treated A431 and WISH cells incorporated significantly less [3H]arachidonic acid into membrane phospholipids than control cells. Finally, genistein decreased the specific activity of prostaglandin H2 synthase prepared from A431 cells, WISH cells, and ram seminal vesicle. The IC50 of genistein for inhibition of prostaglandin H2 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.
Kniss
D A
DA
Department of Obstetrics & Gynecology, Ohio State University, College of Medicine, Columbus 43210-1228, USA.
Zimmerman
P D
PD
Su
H C
HC
Fertel
R H
RH
D016475:3T3 Cells; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors*; D019833:Genistein; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D010743:Phospholipids / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007529:Isoflavones; D008563:Membrane Lipids; D010743:Phospholipids; D016718:Arachidonic Acid; D004815:Epidermal Growth Factor; D019833:Genistein; D020794:Receptor Protein-Tyrosine Kinases; D015232:Dinoprostone