6533b825fe1ef96bd1282ebb

RESEARCH PRODUCT

La galectine-9 se lie aux récepteurs agonistes de TRAIL et régule l'apoptose induite par TRAIL

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APO2L/TRAIL (TNF-related apoptosis-inducing ligand) arouses great interest in cancer therapy. This protein induces apoptosis in tumor cells through DR4 or DR5, two transmembrane glycoproteins that harbor N- and O- glycosylations, respectively. The glycosylation of DR4 or DR5 receptors is likely to allow unforseen protein/protein interactions. For instance, galectins, owing to their ability to bind to oligosaccharides, can interact with glycoproteins, and are therefore potentially able to regulate TRAIL pro-apoptotic machinery in tumor cells. Given in addition that conventional chemotherapeutic drugs such as 5-fluorouracil (5FU), often restore or increase TRAIL-induced apoptosis, but that the molecular mechanism underlying this gain of function remains elusive, we investigated the possibility that galectins may link restoration of TRAIL sensitivity upon sequential chemotherapy. We provide evidence, here, that 5FU sensitizes tumor cells to TRAIL-induced apoptosis through its ability to induce the secretion of galectin-9 into the extracellular medium. Mechanistically, the binding of secreted galectin-9 with the extracellular domains of DR4 and/or DR5, increased apoptosis triggered by TRAIL. This gain of function and interaction was strictly related to the sugar moiety harbored by DR4 and DR5. Likewise, point mutations of the glycosylation sites or production of the receptors in prokaryotic cells not only abrogated galectin-3 and 9 binding, but also restoration of TRAIL sensitivity by 5FU. However, when the receptors are properly glycosylated, overexpression of galectins or addition of soluble recombinant of galectin-3 or -9 alone, is sufficient to increase tumor cell sensitivity to TRAIL-induced cell death. Overall, our results suggest that galectins are novel components of TRAIL's DISC whose regulation by 5FU helps explain, at least in part, how this conventional chemotherapy increases the therapeutic potential of TRAIL.