Intervention of a Communication Between PI3K/Akt and β‐Catenin by (−)‐Epigallocatechin‐3‐Gallate Suppresses TGF‐β1‐Promoted Epithelial‐Mesenchymal Transition and Invasive Phenotype of NSCLC Cells

ABSTRACT The epithelial‐mesenchymal transition (EMT) assists in the acquisition of invasiveness, relapse, and resistance in non‐small cell lung cancer (NSCLC) and can be caused by the signaling of transforming growth factor‐β1 (TGF‐β1) through Smad‐mediated or Smad‐independent pathways. (−)‐Epigallocatechin‐3‐gallate (EGCG), a multifunctional cancer‐preventing bioconstituent found in tea polyphenols, has been shown to repress TGF‐β1‐triggered EMT in the human NSCLC A549 cell line by inhibiting the activation of Smad2 and Erk1/2 or reducing the acetylation of Smad2 and Smad3. However, its impact on the Smad‐independent pathway remains unclear. Here, we found that EGCG, similar to LY294002 (a specific inhibitor of phosphatidylinositol 3‐kinase [PI3K]), downregulated Akt activation and restored the action of glycogen synthase kinase‐3β (GSK‐3β), accompanied by TGF‐β1‐caused changes in hallmarks of EMT such as N‐cadherin, E‐cadherin, vimentin, and Snail in A549 cells. EGCG inhibited β‐catenin expression and its nuclear localization caused by TGF‐β1, suggesting that EGCG blocks the crosstalk between the PI3K/Akt/GSK‐3β route and β‐catenin. Furthermore, it was shown that EGCG suppressed TGF‐β1‐elicited invasive phenotypes of A549 cells, including invading and migrating activities, matrix metalloproteinase‐2 (MMP‐2) secretion, cell adhesion, and wound healing. In summary, we suggest that EGCG inhibits the induction of EMT by TGF‐β1 in NSCLC not only through a Smad‐dependent pathway, but also through the regulation of the PI3K/Akt/β‐catenin signaling axis.