Suppression of beta-catenin signaling in colon carcinoma cells by a bacterial protein
Menée à l'aide de lignées cellulaires et d'un modèle murin de cancer du côlon, cette étude met en évidence l'intérêt thérapeutique d'une injection intratumorale de MakA, une protéine bactérienne, et analyse le mécanisme d'action de cette protéine
Colorectal cancer is one of the leading causes of cancer‐related death worldwide. The adenomatous polyposis coli (APC) gene is mutated in hereditary colorectal tumors and in more than 80% of sporadic colorectal tumors. APC mutations impair
β
‐catenin degradation, leading to its permanent stabilization and increased transcription of cancer‐driving target genes. In colon cancer, impairment of
β
‐catenin degradation leads to its cytoplasmic accumulation, nuclear translocation, and subsequent activation of tumor cell proliferation. Suppressing
β
‐catenin signaling in cancer cells therefore appears to be a promising strategy for new anti‐cancer strategies. Recently, we discovered a novel Vibrio cholerae cytotoxin, MakA, that affects both invertebrate and vertebrate hosts. It promotes bacterial survival and proliferation in invertebrate predators but has unknown biological role(s) in mammalian hosts. Here, we report that MakA can cause lethality of tumor cells via induction of apoptosis. Interestingly, MakA exhibited potent cytotoxic activity, in particular against several tested cancer cell lines, while appearing less toxic towards non‐transformed cells. MakA bound to the tumor cell surface became internalized into the endolysosomal compartment, and induced leakage of endolysosomal membranes, causing cytosolic release of cathepsins and activation of proapoptotic proteins. In addition, MakA altered
β
‐catenin integrity in colon cancer cells, partly through a caspase‐ and proteasome‐dependent mechanism. Importantly, MakA inhibited
β
‐catenin‐mediated tumor cell proliferation. Remarkably, intratumor injection of MakA significantly reduced tumor development in a colon cancer murine solid tumor model. These data identify MakA as a novel candidate to be considered in new strategies for development of therapeutic agents against colon cancer.