title: Fisetin regulates TPA-induced breast cell invasion by suppressing matrix metalloproteinase-9 activation via the PKC/ROS/MAPK pathways.
abstract: Invasion and metastasis are among the main causes of death in patients with malignant tumors. Fisetin (3,3',4',7-tetrahydroxyflavone), a natural flavonoid found in the smoke tree (Cotinus coggygria), is known to have antimetastatic effects on prostate and lung cancers; however, the effect of fisetin on breast cancer metastasis is unknown. The aim of this study was to determine the anti-invasive activity of fisetin in human breast cancer cells. Matrix metalloproteinase (MMP)-9 is a major component facilitating the invasion of many cancer tumor cell types, and thus the inhibitory effect of fisetin on MMP-9 expression in 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated human breast cancer cells was investigated in this study. Fisetin significantly attenuated TPA-induced cell invasion in MCF-7 human breast cancer cells, and was found to inhibit the activation of the PKCα/ROS/ERK1/2 and p38 MAPK signaling pathways. This effect was furthermore associated with reduced NF-κB activation, suggesting that the anti-invasive effect of fisetin on MCF-7 cells may result from inhibited TPA activation of NF-κB and reduced TPA activation of PKCα/ROS/ERK1/2 and p38 MAPK signals, ultimately leading to the downregulation of MMP-9 expression. Our findings indicate the role of fisetin in MCF-7 cell invasion, and clarify the underlying molecular mechanisms of this role, suggesting fisetin as a potential chemopreventive agent for breast cancer metastasis.
authors.affiliation: Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan 570-749, South Korea.
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Noh
authors.affiliation: Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan 570-749, South Korea.
authors.forename: Yeon-Ju
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan 570-749, South Korea.
authors.forename: Jeong-Mi
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan 570-749, South Korea.
authors.forename: Mi-Seong
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan 570-749, South Korea.
authors.forename: Ha-Rim
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan 570-749, South Korea.
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Song
authors.affiliation: Department of Biochemistry, Institute of Medical Science, Chonbuk National University Medical School, Jeonju 560-182, South Korea.
authors.forename: On-Yu
authors.initials: OY
authors.lastname: Hong
authors.affiliation: Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan 570-749, South Korea.
authors.forename: Hong-Seob
authors.initials: HS
authors.lastname: So
authors.affiliation: Department of Internal Medicine, Wonkwang University School of Medicine, Iksan 570-749, South Korea.
authors.forename: Sei-Hoon
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, Institute of Medical Science, Chonbuk National University Medical School, Jeonju 560-182, South Korea.
authors.forename: Jong-Suk
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Jeonbuk 580-185, South Korea; Department of Radiation Biotechnology and Applied Radioisotope Science, Korea University of Science and Technology, Daejeon 305-350, South Korea.
authors.forename: Samg Hyun
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Surgery, Division of Breast and Thyroid Surgery, Chonbuk National University Medical School, Jeonju 560-182, South Korea.
authors.forename: Hyun-Jo
authors.initials: HJ
authors.lastname: Youn
authors.affiliation: Department of Oral Biochemistry, and Institute of Biomaterials, Implant, School of Dentistry, Wonkwang University, Iksan 570-749, South Korea.
authors.forename: Yong-Ouk
authors.initials: YO
authors.lastname: You
authors.affiliation: KI-BANG's Korean Medicine Clinic, Byung-Jum-Dong, Hwasung, Gyunggi-Do 445-360, South Korea.
authors.forename: Ki-Bang
authors.initials: KB
authors.lastname: Choi
authors.affiliation: Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan 570-749, South Korea; Department of Korean Physiology, Wonkwang University School of Korean Medicine, Iksan 570-749, South Korea. Electronic address: desson@wku.ac.kr.
authors.forename: Kang-Beom
authors.initials: KB
authors.lastname: Kwon
authors.affiliation: Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan 570-749, South Korea; Department of Oral Biochemistry, and Institute of Biomaterials, Implant, School of Dentistry, Wonkwang University, Iksan 570-749, South Korea. Electronic address: mindyr@wku.ac.kr.
authors.forename: Young-Rae
authors.initials: YR
authors.lastname: Lee
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D061986:MCF-7 Cells; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D051571:Protein Kinase C-alpha / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
chemical_list: D005419:Flavonoids; D044948:Flavonols; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D004247:DNA; D051571:Protein Kinase C-alpha; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate; C017875:fisetin
keywords: Fisetin; Invasion; MCF-7; MMP-9; PKCα