The molecular and phenotypic associations between chemo- or radio-resistance and the acquisition of epithelial-mesenchymal transition (EMT)-like phenotype are tightly related in cancer cells. Wnt/β- catenin and NF-κB signaling pathways play crucial roles in EMT induction. Apicidin-resistant (Apicidin- R) HA22T cells are known to activate the Wnt/β-catenin signaling pathway and MMP-2 expression via the IGF-IR/PI3K/Akt signaling pathway to enhance metastatic effects of cancer cells. In this study, we further investigated if Apicidin-R HA22T cells actually underwent EMT. In Apicidin-R HA22T cells, E-cadherin protein level was reduced but Vimentin, Snail and Twist were significantly activated. Activation of p-IKKαβ and p-IκBα was also observed in Apicidin-R HA22T cells. Apicidin-R HA22T cells displayed even higher NF-κB nuclear accumulation. Snail was enhanced but GSK3-β was reduced. However, unphosphorylated GSK3-β protein level was totally reversed when the Snail-specific siRNA was applied in a knockdown experiment. Taken together, Apicidin-R HA22T cells could potentiate aggressive metastasis behavior due to up-regulation of Snail expression and promoted EMT effects via the IKKαβ/NF-κB pathway. In addition, Snail might decrease the GSK3-β level resulting in extraordinarily activation of Wnt/β-catenin signaling pathway.