Effects of Flavonoids on MMPs Secretion and Invadopodia Formation in Highly Invasive A431-III Epidermal Cancer Cells
Date Issued
2012
Date
2012
Author(s)
Lin, Yo-Chuen
Abstract
Metastasis is the major cause of mortality in cancer patients and is a complex, multi-step process. Local invasion is the very first step in cancer metastasis. Invadopodia, which are actin-rich membrane protrusions of invasive cancer cells, are responsible for this invasive process. Invadopodia can extend into the extracellular matrix by recruiting matrix metalloproteinases (MMPs) and releasing them; invadopodia are now believed to be crucial structures that allow cancer cells to degrade and penetrate across the extracellular matrix (ECM). We previously obtained a highly invasive A431-III cell sub-line by using the Boyden chamber assay. The A431-III cell line exhibits higher invasive and migratory characteristics. In addition, A431-III exhibits elevated MMP-9 level and epithelial-mesenchymal transition (EMT) phenotype. Thus, this cell line is a reliable model for studying the mechanism of metastasis/invasion. Herein, we showed that A431-III exerted greater ability to form invadopodia leading to more degradation of the ECM than A431 cells. Cortactin, Src, and their phosphorylation have been reported as main regulator of invadopodia formation and function. Our data revealed that the phosphorylation of cortactin (Y421) and Src (Y418) were increased in A431-III cells. Since the degrading ability of invadopodia needs participation of proteases, we also showed the importance of MMPs, especially MMP-9, in this degrading event.
Flavonoids, a large group of plant secondary metabolites, are present in almost all-higher plants and display a wide range of pharmacodynamic properties including anti-inflammatory, anti-carcinogenic and anti-metastatic effects. We previously screened out two of the most potent flavonoids, luteolin and quercetin, which can suppress cancer invasion and MMPs secretion. Since it is known that the secretion of MMPs is targeted at invadopodia, our study showed that treating with luteolin and quercetin inhibited the formation of invadopodia in A431-III and decreased the ability of ECM degradation as well. Our data further revealed that these two flavonoids could inhibit Src kinase and the phosphorylation of cortactin, which in turn disrupt the formation of invadopodia. Followed by our previous study that flavonoids inhibited MMPs secretion, these results may explain in part how flavonoids affect MMPs secretion and metastasis potential.
Flavonoids, a large group of plant secondary metabolites, are present in almost all-higher plants and display a wide range of pharmacodynamic properties including anti-inflammatory, anti-carcinogenic and anti-metastatic effects. We previously screened out two of the most potent flavonoids, luteolin and quercetin, which can suppress cancer invasion and MMPs secretion. Since it is known that the secretion of MMPs is targeted at invadopodia, our study showed that treating with luteolin and quercetin inhibited the formation of invadopodia in A431-III and decreased the ability of ECM degradation as well. Our data further revealed that these two flavonoids could inhibit Src kinase and the phosphorylation of cortactin, which in turn disrupt the formation of invadopodia. Followed by our previous study that flavonoids inhibited MMPs secretion, these results may explain in part how flavonoids affect MMPs secretion and metastasis potential.
Subjects
invasion
invadopodia
MMPs
Src
cortactin
flavonoids
SDGs
Type
thesis
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