Films from Figyre 6B

Description

Abstract

Bacterial genotoxins, Cytolethal Distending Toxin (CDT) and colibactin, cause DNA damage in intoxicated epithelial cells of the host. DNA damage influences β‑catenin signaling, altering its stability and nuclear translocation, potentially contributing to cancer development. Using non-transformed hepatocytes and cancer-derived intestinal and hepatic epithelial cell lines, we showed that CDT/CdtB induces the phosphorylation of β‑catenin at serine 552, along with the loss of β‑catenin from adherens junctions. This leads to the subsequent cytoplasmic accumulation and nuclear translocation of β‑catenin, ultimately driving TCF/LEF transcription, the crucial downstream event of Wnt/β‑catenin signaling, as well as the transcription of some β‑catenin target genes. Colibactin induces similar effects. MK‑2206, a direct AKT inhibitor, and metformin, an AMP-activated protein kinase activator that indirectly inhibits AKT, both protected cells against various effects induced by CdtB exposure. These effects include β‑catenin phosphorylation at Ser552, the disassembly of cell-cell junctions and the subsequent nuclear accumulation of phosphorylated β‑catenin, leading to reduced TCF/LEF-mediated transcription. Additionally, MK‑2206 and metformin protected from CdtB-induced epithelial–mesenchymal transition (EMT), including increased nuclear accumulation of SNAIL, enhanced matrix degradation and motility. Overall, these data show that infection with genotoxin-producing bacteria controls some EMT features through β‑catenin and AKT-dependent signaling.