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bioRxiv · 10.64898/2026.06.01.729203

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

JIA, R.·Azzi-Martin, L.·Saraiva, M.·Sifre, E.·Varon, C.·Dubus, P.·Menard, A.
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Abstract

Bacterial genotoxins, Cytolethal Distending Toxin (CDT) and colibactin, cause DNA damage in intoxicated epithelial cells of the host. DNA damage influences {beta}-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 {beta}-catenin at serine 552, along with the loss of {beta}-catenin from adherens junctions. This leads to the subsequent cytoplasmic accumulation and nuclear translocation of {beta}-catenin, ultimately driving TCF/LEF transcription, the crucial downstream event of Wnt/{beta}-catenin signaling, as well as the transcription of some {beta}-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 {beta}-catenin phosphorylation at Ser552, the disassembly of cell-cell junctions and the subsequent nuclear accumulation of phosphorylated {beta}-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 {beta}-catenin and AKT-dependent signaling.

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JIA, R., Azzi-Martin, L., Saraiva, M., Sifre, E., Varon, C., Dubus, P., Menard, A.. 2026-06-03. Cytolethal distending toxin promotes epithelial-to-mesenchymal transition by modulating AKT-Dependent β-catenin Ser552 phosphorylation. https://doi.org/10.64898/2026.06.01.729203

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