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Carcinogenesis Advance Access published online on July 14, 2008
Carcinogenesis, doi:10.1093/carcin/bgn162
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Quercetin inhibition of tumor invasion via suppressing PKC{delta}/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells

Cheng-Wei Lina, Wen-Chi Houb, Shing-Chuan Shenc, Shu-Hui Juanc, Ching-Huai Kod, Ling-Mei Wangd and Yen-Chou Chenc,e,*

a Graduate Institute of Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
b Graduate Institute of Pharmacognosy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
c Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
d Cell Engineering Lab, Biomedical Engineering Research Laboratories, The Industrial Technology Research Institute, Hsing-Chu, Taiwan
e Cancer Research Center and Orthopedics Research Center, Taipei Medical University Hospital, Taipei, Taiwan

* Corresponding author: Dr. Yen-Chou Chen, Tel: 886-2-27361661 ext. 3421. Fax: 886-2-23787139. E-mail: yc3270{at}tmu.edu.tw (Y.C. Chen)

Quercetin (3,5,7,3',4'-tetrahydroxyflavone; QUE) has been shown to possess several beneficial biological activities including anti-tumor, anti-inflammation, and antioxidant properties; however, the effects of QUE in preventing invasion by breast carcinoma cells are still undefined. Increases in the protein, mRNA, and enzyme activity levels of matrix metalloproteinase-9 (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 (QUI) or rutin (RUT). A translocation of protein kinase C (PKC){delta} from the cytosol to the membrane followed by activation of ERK and c-Jun/AP-1 by TPA was demonstrated, and TPA-induced MMP-9 activation and migration were inhibited by the pan PKC inhibitor, GF109203X (GF), the specific PKC{delta} inhibitor, rottlerin (Rot), an ERK inhibitor (PD98059), and an AP-1 inhibitor (curcumin). Application of QUE significantly suppressed TPA-induced activation of the PKC{delta}/ERK/AP-1 signaling cascade. To elucidate the importance of 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 anti-tumor invasion and migration effects of breast carcinoma cells induced by QUE with the structure-activity relationship analysis were identified.

Key Words: Quercetin • Flavonoids • Invasion • MMP-9 • Breast cancer

Received April 2, 2008; revised June 19, 2008; accepted July 5, 2008.


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