1,2,3,6-Tetra-O-Galloyl-β-D-Glucopyranose Induces Apoptosis and Ferroptosis in Colon Cancer Cells by Inhibiting the Wnt/β-Catenin Signaling Pathway.

Molecular irregularities in the canonical Wnt pathway that lead to the stabilization of β-catenin are common in colon cancer. Here, we identified 1,2,3,6-Tetra-O-galloyl-β-D-glucopyranose (TAGP), separated from Trapa japonica, as an inhibitor of canonical Wnt signaling. TAGP facilitated the phosphorylation of Ser33/37 and the degradation of β-catenin, which had accumulated due to Wnt3a-conditioned medium or the inhibitor 6-bromoindirubin-3'-oxime that targets glycogen synthase kinase-3β (GSK-3β). Additionally, TAGP lowered the levels of Cyclin D1 and c-Myc, which are regulated by β-catenin/T-cell factor (TCF) and showed antiproliferative activity in colon cancer cells. Furthermore, TAGP triggered apoptosis, as demonstrated by the activation of caspases 3 and 7, in conjunction with raising the number of Annexin-V-positive cells. It also promoted ferroptosis, as shown by the buildup of lipid peroxides and Fe²⁺ in the cells. Taken together, TAGP enhances β-catenin turnover, indicating its potential as a chemotherapeutics for colon cancer in humans.