PrP^c deficiency and dasatinib protect mouse intestines against radiation injury by inhibiting of c-Src

Background & Aim Despite extensive study of the contribution of cell death and apoptosis to radiation-induced acute intestinal injury, our knowledge of the signaling mechanisms involved in epithelial barrier dysfunction remains inadequate. Because PrP^c plays a key role in intestinal homeostasis by renewing epithelia, we sought to study its role in epithelial barrier function after irradiation. Design Histology, morphometry and plasma FD-4 levels were used to examine ileal architecture, wound healing, and intestinal leakage in PrP^c-deficient (KO) and wild-type (WT) mice after total-body irradiation. Impairment of the PrP^c Src pathway after irradiation was explored by immunofluorescence and confocal microscopy, with Caco-2/Tc7 cells. Lastly, dasatinib treatment was used to switch off the Src pathway in vitro and in vivo. Results The decrease in radiation-induced lethality, improved intestinal wound healing, and reduced intestinal leakage promoted by PrP^c deficiency demonstrate its involvement in acute intestinal damage. Irradiation of Cacao2/Tc7 cells induced PrP^c to target the nuclei associated with Src activation. Finally, the protective effect triggered by dasatinib confirmed Src involvement in radiation-induced acute intestinal toxicity. Conclusion Our data are the first to show a role for the PrP^c-Src pathway in acute intestinal response to radiation injury and offer a novel therapeutic opportunity.