Docosahexaenoic acid inhibits 12-O-tetradecanoylphorbol-13- acetate-induced fascin-1-dependent breast cancer cell migration by suppressing the PKC?- and Wnt-1/?-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 PKC? and STAT3? activation and GSK3? phosphorylation; up-regulated Wnt-1, ?-catenin, and STAT3? expression; and increased the nuclear translocation of ?-catenin and STAT3?. Rottlerin, a PKC? inhibitor, abrogated the increases in STAT3? activation and ?-catenin and fascin-1 expression. WP1066, a STAT3 inhibitor, suppressed TPA-induced STAT3? DNA binding activity and ?-catenin expression. Knockdown of ?-catenin attenuated TPA-induced fascin-1 and STAT3? expression as well as cell migration. In addition to MCF-7, migration of Hs578T breast cancer cells was inhibited by silencing fascin-1, ?-catenin, and STAT3? expression as well. TPA also induced Wnt-1 expression and secretion, and blocking Wnt-1 signaling abrogated ?-catenin induction. DHA pretreatment attenuated TPA-induced cell migration, PKC? and STAT3? activation, GSK3? phosphorylation, and Wnt-1, ?-catenin, STAT3?, and fascin-1 expression. Our results demonstrated that TPA-induced migration is likely associated with the PKC? and Wnt-1 pathways, which lead to STAT3? activation, GSK3? inactivation, and ?-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 PKC? and Wnt-1 signaling.

SUBMITTER: Lii CK 

PROVIDER: S-EPMC5041895 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature