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Ursolic Acid Inhibits Cyclooxygenase-2 Transcription in Human Mammary Epithelial Cells¹

Department of Medicine [K. S., A. J. D.] and Surgery [K. S., A. J. D.], New York Presbyterian Hospital-Cornell, New York, New York 10021, USA; Anne Fisher Nutrition Center [K. S., A. J. D.] at Strang Cancer Prevention Center, New York, New York 10021, USA; and Head and Neck Service [P. M.], Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA, and Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA [M. B. S.]

We investigated the effects of ursolic acid, a chemopreventive agent, on the expression of cyclooxygenase-2 (COX-2) in phorbol 12-myristate 13-acetate (PMA)-treated human mammary and oral epithelial cells. Treatment with ursolic acid suppressed PMA-mediated induction of COX-2 protein and synthesis of prostaglandin E₂. Ursolic acid also suppressed the induction of COX-2 mRNA by PMA. Nuclear run-offs revealed increased rates of COX-2 transcription after treatment with PMA, an effect that was inhibited by ursolic acid. Transient transfections indicated that the effects of PMA were mediated by a cyclic AMP response element in the COX-2 promoter. Ursolic acid inhibited PMA-mediated activation of protein kinase C, extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinases. Treatment with PMA increased activator protein-1 activity and the binding of c-Jun to the cyclic AMP response element of the COX-2 promoter, effects that were blocked by ursolic acid. These data are important for understanding the anticancer and anti-inflammatory properties of ursolic acid.

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