Quercetin inhibition of tumor invasion via suppressing PKC delta/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells.
Quercetin (QUE; 3,5,7,3',4'-tetrahydroxyflavone) has been shown to possess several beneficial biological activities including antitumor, anti-inflammation and antioxidant properties; however, the effects of QUE in preventing invasion by breast carcinoma cells are still undefined. Increases in the protein, messenger RNA and enzyme activity levels of matrix metalloproteinase (MMP)-9 were observed in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated MCF-7 cells, and these were blocked by QUE, but not by quercitrin or rutin. A translocation of protein kinase C (PKC)delta from the cytosol to the membrane followed by activation of extracellular signal-regulated kinase (ERK) and c-Jun/activator protein-1 (AP-1) by TPA was demonstrated, and TPA-induced MMP-9 activation and migration were inhibited by the pan PKC inhibitor, GF109203X, the specific PKCdelta inhibitor, rottlerin, an ERK inhibitor (PD98059) and an AP-1 inhibitor (curcumin). Application of QUE significantly suppressed TPA-induced activation of the PKCdelta/ERK/AP-1-signaling cascade. To elucidate the importance of hydroxyl (OH) substitutions to QUE's inhibition of tumor migration, several structurally related flavones of QUE including 3',4'-diOH, 3',4'-diOCH(3), 3,5,7-triOH, 3,4',4'-triOH, 3,3',4'-triOCH(3), luteolin and fisetin were used. Results suggested that OH groups at both C3' and C4' play central roles in QUE's inhibition of TPA-induced MMP-9 activation and migration, and an additional OH at C3, C5 or C7 may increase the inhibitory potency of the 3',4'-diOH flavone against TPA-induced MMP-9 activity and migration. The antitumor invasion and migration effects of breast carcinoma cells induced by QUE with the structure-activity relationship analysis were identified.
Lin
Cheng-Wei
CW
Graduate Institute of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
Hou
Wen-Chi
WC
Shen
Shing-Chuan
SC
Juan
Shu-Hui
SH
Ko
Ching-Huai
CH
Wang
Ling-Mei
LM
Chen
Yen-Chou
YC
D001713:Biphenyl Compounds / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D002273:Carcinogens / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010851:Picrates; D051745:Protein Kinase C-delta / Q000378:metabolism*; D011794:Quercetin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
D001713:Biphenyl Compounds; D002273:Carcinogens; D006834:Hydrazines; D061965:Matrix Metalloproteinase Inhibitors; D010851:Picrates; D018808:Transcription Factor AP-1; C012526:quercitrin; D017665:Hydroxyl Radical; D011794:Quercetin; C004931:1,1-diphenyl-2-picrylhydrazyl; D051745:Protein Kinase C-delta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate