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.
Highlights
Metastasis is the most common cause of poor prognosis and worse survival rates in cancer patients
To verify that fascin-1 plays an important role in breast cancer cell migration, MCF-7 cells were treated with tetradecanoylphorbol 13-acetate (TPA) and Western blotting and the wound healing assay were performed
These findings indicated that induction of fascin-1 is important in TPA-induced MCF-7 cell migration and that the anti-migration effect of Docosahexaenoic acid (DHA) is likely associated with the suppression of this actin filament bundling protein
Summary
Metastasis is the most common cause of poor prognosis and worse survival rates in cancer patients. A meta-analysis reported that fascin, an actin-bundling protein, is consistently associated with increased risk of metastasis and mortality in numerous carcinomas, such as the gastric, colorectal, and breast cancers [1]. The fascin protein family consists of three subtypes: fascin-1, fascin-2, and fascin-3 [2]. Fascin-1, is expressed in various cell types in normal tissues. Fascin expression is induced by a variety of cytokines such as www.impactjournals.com/oncotarget interleukin-6 (IL-6) and oncostatin M via transactivation of signal transducers and activators of transcription 3 (STAT3) in breast cancer cells [6]. Transcription factors such as nuclear factor κB (NFκB) and hypoxia-inducible factor promote fascin gene transcription [7, 8]
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