Cytolethal distending toxin promotes epithelial-to-mesenchymal transition by modulating AKT-Dependent β-catenin Ser552 phosphorylation
Abstract
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…
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