title: Docosahexaenoic acid inhibits 12-O-tetradecanoylphorbol-13- acetate-induced fascin-1-dependent breast cancer cell migration by suppressing the PKCδ- and Wnt-1/β-catenin-mediated pathways.
abstract: Fascin-1, an actin-bundling protein, plays an important role in cancer cell migration and invasion; however, the underlying mechanism remains unclear. On the basis of a 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced cell migration model, it was shown that TPA increased fascin-1 mRNA and protein expression and fascin-1-dependent cell migration. TPA dose- and time-dependently increased PKCδ and STAT3α activation and GSK3β phosphorylation; up-regulated Wnt-1, β-catenin, and STAT3α expression; and increased the nuclear translocation of β-catenin and STAT3α. Rottlerin, a PKCδ inhibitor, abrogated the increases in STAT3α activation and β-catenin and fascin-1 expression. WP1066, a STAT3 inhibitor, suppressed TPA-induced STAT3α DNA binding activity and β-catenin expression. Knockdown of β-catenin attenuated TPA-induced fascin-1 and STAT3α expression as well as cell migration. In addition to MCF-7, migration of Hs578T breast cancer cells was inhibited by silencing fascin-1, β-catenin, and STAT3α expression as well. TPA also induced Wnt-1 expression and secretion, and blocking Wnt-1 signaling abrogated β-catenin induction. DHA pretreatment attenuated TPA-induced cell migration, PKCδ and STAT3α activation, GSK3β phosphorylation, and Wnt-1, β-catenin, STAT3α, and fascin-1 expression. Our results demonstrated that TPA-induced migration is likely associated with the PKCδ and Wnt-1 pathways, which lead to STAT3α activation, GSK3β inactivation, and β-catenin increase and up-regulation of fascin-1 expression. Moreover, the anti-metastatic potential of DHA is partly attributed to its suppression of TPA-activated PKCδ and Wnt-1 signaling.
authors.affiliation: Department of Nutrition, China Medical University, Taichung, Taiwan.|Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Chong-Kuei
authors.initials: CK
authors.lastname: Lii
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institute, Zhunan, Miaoli, Taiwan.
authors.forename: Jer-Wei
authors.initials: JW
authors.lastname: Chang
authors.affiliation: School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Jia-Jing
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Department of Nutrition, China Medical University, Taichung, Taiwan.
authors.forename: Haw-Wen
authors.initials: HW
authors.lastname: Chen
authors.affiliation: School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.|Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Kai-Li
authors.initials: KL
authors.lastname: Liu
authors.affiliation: School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.|Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Shu-Lan
authors.initials: SL
authors.lastname: Yeh
authors.affiliation: Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Tsu-Shing
authors.initials: TS
authors.lastname: Wang
authors.affiliation: School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Liu
authors.affiliation: School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chia-Han
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.|Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Chien-Chun
authors.initials: CC
authors.lastname: Li
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002273:Carcinogens / Q000633:toxicity; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D002273:Carcinogens; D002352:Carrier Proteins; C502658:FSCN1 protein, human; D008840:Microfilament Proteins; D004281:Docosahexaenoic Acids; D051745:Protein Kinase C-delta; D013755:Tetradecanoylphorbol Acetate
keywords: PKCδ; TPA; Wnt-1; docosahexaenoic acid; fascin-1