Curcumin inhibits phorbol ester-induced up-regulation of cyclooxygenase-2 and matrix metalloproteinase-9 by blocking ERK1/2 phosphorylation and NF-kappaB transcriptional activity in MCF10A human breast epithelial cells.
Elevated levels of cyclooxygenase-2 (COX-2) and matrix metalloproteinases (MMPs) are often observed in various types of cancerous and transformed cells, and hence recognized as potential molecular targets for the chemoprevention. In the present study, we investigated the possible inhibitory effects of curcumin on the expression of COX-2 and MMP-9 induced by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) in MCF10A human breast epithelial (MCF10A) cells and the underlying mechanisms. Curcumin inhibited the TPA-induced COX-2 expression at both transcriptional and post-transcriptional levels, and reduced the synthesis of prostaglandin E(2), one of the major products of COX-2. Likewise, curcumin attenuated invasiveness and motility of MCF10A cells stimulated with TPA through suppression of MMP expression. Curcumin blocked TPA-induced activation of extracellular signal-regulated protein kinase (ERK1/2) and nuclear factor kappaB (NF-kappaB) transcriptional activity. Overexpression of the dominant negative forms of ERK2 abrogated the TPA-induced NF-kappaB transcriptional activity. Treatment of MCF10A cells with U0126, which is a pharmacological inhibitor of ERK1/2, reduced TPA-induced up-regulation of COX-2 and MMP-9. Taken together, these findings suggest that curcumin inhibits the TPA-induced up-regulation of COX-2 and MMP-9 by suppressing ERK1/2 phosphorylation and NF-kappaB trans-activation in human breast epithelial cells, which may contribute to its chemopreventive potential.
Lee
Ki Won
KW
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Kim
Jung-Hwan
JH
Lee
Hyong Joo
HJ
Surh
Young-Joon
YJ
D001940:Breast / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D002384:Catalysis; D002460:Cell Line; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D016328:NF-kappa B; D010703:Phorbol Esters; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9; D003474:Curcumin; D015232:Dinoprostone