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

Abstract 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 PrPc plays a key role in intestinal hom...

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Published in:Radiotherapy and oncology 2016-07, Vol.120 (1), p.175-183
Main Authors: Strup-Perrot, Carine, Vozenin, Marie-Catherine, Monceau, Virginie, Pouzoulet, Frederic, Petit, Benoit, Holler, Valérie, Perrot, Sébastien, Desquibert, Loïc, Fouquet, Stéphane, Souquere, Sylvie, Pierron, Gérard, Rousset, Monique, Thenet, Sophie, Cardot, Philippe, Benderitter, Marc, Deutsch, Eric, Aigueperse, Jocelyne
Format: Article
Language:English
Subjects:
Hematology, Oncology and Palliative Medicine
Intestinal wound healing
Irradiation
Life Sciences
Mouse model
Permeability
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Summary:Abstract 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 PrPc 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 PrPc -deficient (KO) and wild-type (WT) mice after total-body irradiation. Impairment of the PrPc 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 PrPc deficiency demonstrate its involvement in acute intestinal damage. Irradiation of Cacao2/Tc7 cells induced PrPc 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 PrPc -Src pathway in acute intestinal response to radiation injury and offer a novel therapeutic opportunity.
ISSN:0167-8140
1879-0887
DOI:10.1016/j.radonc.2016.06.009