Carcinogenesis Advance Access originally published online on July 14, 2008
Carcinogenesis 2008 29(9):1807-1815; doi:10.1093/carcin/bgn162
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Quercetin inhibition of tumor invasion via suppressing PKC
/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells
1 Graduate Institute of Pharmacy
2 Graduate Institute of Pharmacognosy, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
3 Graduate Institute of Medical Sciences, Taipei Medical University, Taipei 110, Taiwan
4 Cell Engineering Lab, Biomedical Engineering Research Laboratories, Industrial Technology Research Institute, Hsing-Chu 310, Taiwan
5 Cancer Research Center and Orthopedics Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan
* To whom correspondence should be addressed. Tel: +886 2 27361661 ext. 3421; Fax: +886 2 23787139; Email: yc3270{at}tmu.edu.tw
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)
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 PKC inhibitor, rottlerin, an ERK inhibitor (PD98059) and an AP-1 inhibitor (curcumin). Application of QUE significantly suppressed TPA-induced activation of the PKC/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'-diOCH3, 3,5,7-triOH, 3,4',4'-triOH, 3,3',4'-triOCH3, 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.
Abbreviations: AP-1, activator protein-1; DPPH, 1,1-diphenyl-2-picrylhydrazyl; ERK, extracellular signal-regulated kinase; Fis, fisetin; GF, GF109203X; Go, Go6976; JNK, c-Jun N-terminal kinase; Lut, luteolin; LY, LY294002; MAPK, mitogen-activated protein kinase; MEM, modified Eagle’s medium; MMP, matrix metalloproteinase; NF-
B, nuclear factor- B; OH, hydroxyl; PD, PD98059; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; QUE, quercetin; QUI, quercitrin; Rot, rottlerin; RUT, rutin; SAR, structure–activity relationship; SB, SB203580; SP, SP600125; TPA, 12-O-tetradecanoylphorbol-13-acetate
Received April 2, 2008; revised June 19, 2008; accepted July 5, 2008.