4-Shogaol, an Active Constituent of Dietary Ginger, Inhibits Metastasis of MDA-MB-231 Human Breast Adenocarcinoma Cells by Decreasing the Repression of NF-κB/Snail on RKIP

4-Shogaol is one of the phytoconstituents isolated from dried red ginger, which is commercially available to consumers. Some active constituents from ginger have been found to have anti-inflammatory and antioxidant effects, but studies on 4-shogaol have been relatively rare. This is the first report describing the antimetastasis activities of 4-shogaol and the possible mechanisms. This study determined that 4-shogaol inhibits the migration and invasion of MDA-MB-231 and causes inesenchyrnal-epithelial transition (MET). In addition, 4-shogaol suppresses the activation of NF-kappa B and cell migration and invasion induced by TNF-alpha. Furthermore, 4-shogaol has been shown to inhibit the phosphorylation of IKB and the translocation of NF-kappa B/Suail in MDA-MB-231. This study shows that RKIP, an inhibitory molecule of IKK, is up-regulated after 4-shogaol trealment and prolongs the inhibitory effects of 4-shogaol. Inhibition of RKIP by shRNA transfection significantly decreases the inhibitory effect of 4-shogaol on the NE-KB/Snail pathway, together with cell migration and invasion, whereas overexpression of Snail suppresses 4-shogaol-mediated metastasis inhibition and E-cadherin upregulation. Finally, the animal model revealed that 4-shegaol effectively inhibits metastasis of MDA-MB-231 in mice. This study demonstrates that 4-shogaol may be a novel anticancer agent for the the treatment of metastasis in breast cancer.