Journal Article

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

Cheng-Wei Lin, Wen-Chi Hou, Shing-Chuan Shen, Shu-Hui Juan, Ching-Huai Ko, Ling-Mei Wang and Yen-Chou Chen

in Carcinogenesis

Volume 29, issue 9, pages 1807-1815
Published in print September 2008 | ISSN: 0143-3334
Published online July 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn162
Quercetin inhibition of tumor invasion via suppressing PKCδ/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells

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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)δ 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 PKCδ inhibitor, rottlerin, an ERK inhibitor (PD98059) and an AP-1 inhibitor (curcumin). Application of QUE significantly suppressed TPA-induced activation of the PKCδ/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.

Journal Article.  6449 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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