Ursolic acid inhibits cyclooxygenase-2 transcription in human mammary epithelial cells.
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.
Subbaramaiah
K
K
Department of Medicine, New York Presbyterian Hospital-Cornell, New York 10021, USA.
Michaluart
P
P
Sporn
M B
MB
Dannenberg
A J
AJ
D015152:Blotting, Northern; D001940:Breast / Q000201:enzymology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000201:enzymology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010957:Plasmids; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012337:RNA, Ribosomal, 18S / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014062:Tongue Neoplasms / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases; D000097245:Ursolic Acid
D051546:Cyclooxygenase 2; D015232:Dinoprostone; D007527:Isoenzymes; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D012337:RNA, Ribosomal, 18S; D013755:Tetradecanoylphorbol Acetate; D014315:Triterpenes; D048051:p38 Mitogen-Activated Protein Kinases; D000097245:Ursolic Acid; C496540:PTGS2 protein, human