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

// Chong-Kuei Lii 1, 2, * , Jer-Wei Chang 3, * , Jia-Jing Chen 4 , Haw-Wen Chen 1 , Kai-Li Liu 4, 5 , Shu-Lan Yeh 4, 5 , Tsu-Shing Wang 6 , Shu-Hui Liu 4 , Chia-Han Tsai 4 , Chien-Chun Li 4, 5 1 Department of Nutrition, China Medical University, Taichung, Taiwan 2 Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan 3 Institute of Molecular and Genomic Medicine, National Health Research Institute, Zhunan, Miaoli, Taiwan 4 School of Nutrition, Chung Shan Medical University, Taichung, Taiwan 5 Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan 6 Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan * These authors contributed equally to this work Correspondence to: Chien-Chun Li, email: licc@csmu.edu.tw Keywords: fascin-1, TPA, docosahexaenoic acid, PKCδ, Wnt-1 Received: June 30, 2015      Accepted: January 27, 2016      Published: February 10, 2016 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.