title: Impact of flavonoids on matrix metalloproteinase secretion and invadopodia formation in highly invasive A431-III cancer cells.
abstract: Metastasis is a major cause of mortality in cancer patients. Invadopodia are considered to be crucial structures that allow cancer cells to penetrate across the extracellular matrix (ECM) by using matrix metalloproteinases (MMPs). Previously, we isolated a highly invasive A431-III subline from parental A431 cells by Boyden chamber assay. The A431-III cells possess higher invasive and migratory abilities, elevated levels of MMP-9 and an enhanced epithelial-mesenchymal transition (EMT) phenotype. In this study, we discovered that A431-III cells had an increased potential to form invadopodia and an improved capacity to degrade ECM compared with the original A431 cells. We also observed enhanced phosphorylation levels of cortactin and Src in A431-III cells; these phosphorylated proteins have been reported to be the main regulators of invadopodia formation. Flavonoids, almost ubiquitously distributed in food plants and plant food products, have been documented to exhibit anti-tumor properties. Therefore, it was of much interest to explore the effects of flavonoid antioxidants on the metastatic activity of A431-III cells. Exposure of A431-III cells to two potent dietary flavonoids, namely luteolin (Lu) and quercetin (Qu), caused inhibition of invadopodia formation and decrement in ECM degradation. We conclude that Lu and Qu attenuate the phosphorylation of cortactin and Src in A431-III cells. As a consequence, there ensues a disruption of invadopodia generation and the suppression of MMP secretion. These changes, in concert, bring about a reduction in metastasis.
authors.affiliation: Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Yo-Chuen
authors.initials: YC
authors.lastname: Lin
authors.forename: Pei-Hsun
authors.initials: PH
authors.lastname: Tsai
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Lin
authors.forename: Chia-Hsiung
authors.initials: CH
authors.lastname: Cheng
authors.forename: Tsung-Han
authors.initials: TH
authors.lastname: Lin
authors.forename: Kevin P H
authors.initials: KP
authors.lastname: Lee
authors.forename: Kai-Yun
authors.initials: KY
authors.lastname: Huang
authors.forename: Shih-Hsun
authors.initials: SH
authors.lastname: Chen
authors.forename: Jiuan-Jiuan
authors.initials: JJ
authors.lastname: Hwang
authors.forename: Chithan C
authors.initials: CC
authors.lastname: Kandaswami
authors.forename: Ming-Ting
authors.initials: MT
authors.lastname: Lee
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D022081:Cell Surface Extensions / Q000187:drug effects* / Q000378:metabolism; D051356:Cortactin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D047311:Luteolin / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011794:Quercetin / Q000494:pharmacology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051356:Cortactin; D007211:Indoles; C416927:SU 6656; D013449:Sulfonamides; D011794:Quercetin; D019061:src-Family Kinases; D020780:Matrix Metalloproteinase 9; D047311:Luteolin