Research Papers:

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, Jer-Wei Chang, Jia-Jing Chen, Haw-Wen Chen, Kai-Li Liu, Shu-Lan Yeh, Tsu-Shing Wang, Shu-Hui Liu, Chia-Han Tsai and Chien-Chun Li _

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Oncotarget. 2016; 7:25162-25179. https://doi.org/10.18632/oncotarget.7301

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Chong-Kuei Lii1,2,*, Jer-Wei Chang3,*, Jia-Jing Chen4, Haw-Wen Chen1, Kai-Li Liu4,5, Shu-Lan Yeh4,5, Tsu-Shing Wang6, Shu-Hui Liu4, Chia-Han Tsai4, Chien-Chun Li4,5

1Department of Nutrition, China Medical University, Taichung, Taiwan

2Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan

3Institute of Molecular and Genomic Medicine, National Health Research Institute, Zhunan, Miaoli, Taiwan

4School of Nutrition, Chung Shan Medical University, Taichung, Taiwan

5Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan

6Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan

*These authors contributed equally to this work

Correspondence to:

Chien-Chun Li, email: [email protected]

Keywords: fascin-1, TPA, docosahexaenoic acid, PKCδ, Wnt-1

Received: June 30, 2015     Accepted: January 27, 2016     Published: February 10, 2016


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.

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