類黃鹼素對A431癌細胞的基質金屬蛋白酶分泌及侵襲性偽足形成能力之影響

林又權

doi:10.6342/NTU.2012.00411

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類黃鹼素對A431癌細胞的基質金屬蛋白酶分泌及侵襲性偽足形成能力之影響

Effects of Flavonoids on MMPs Secretion and Invadopodia Formation in Highly Invasive A431-III Epidermal Cancer Cells

林又權 , Masters　　Advisor：李明亭　　

英文 DOI： 10.6342/NTU.2012.00411

癌症入侵；侵襲性偽足；基質金屬蛋白酶Src蛋白磷酸酶類黃鹼素； invasion ； invadopodia ； MMPs ； Src ； cortactin ； flavonoids

Abstract │ Reference (111) │ Altmetrics

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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.

Reference ( 111 ) 〈TOP〉

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連結：
Ammer AG, Weed SA (2008) Cortactin branches out: roles in regulating protrusive actin dynamics. Cell Motility and the Cytoskeleton 65: 687-707
連結：
Artym VV, Zhang Y, Seillier-Moiseiwitsch F, Yamada KM, Mueller SC (2006) Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function. Cancer Research 66: 3034-3043
連結：
Ayala I, Baldassarre M, Caldieri G, Buccione R (2006) Invadopodia: a guided tour. European Journal of Cell Biology 85: 159-164
連結：
Ayala I, Baldassarre M, Giacchetti G, Caldieri G, Tete S, Luini A, Buccione R (2008) Multiple regulatory inputs converge on cortactin to control invadopodia biogenesis and extracellular matrix degradation. Journal of Cell Science 121: 369-378
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