Carine Strup-Perrot1, Marie-Catherine Vozenin2, Virginie Monceau3, Frederic Pouzoulet4, Benoit Petit5, Valérie Holler1, Sébastien Perrot6, Loïc Desquibert6, Stéphane Fouquet7, Sylvie Souquere8, Gérard Pierron8, Monique Rousset9, Sophie Thenet10, Philippe Cardot9, Marc Benderitter1, Eric Deutsch11, Jocelyne Aigueperse12. 1. Institut de Radioprotection et de Sûreté Nucléaire, PRP-HOM, SRBE, Laboratoire de Recherche sur la Régénération des tissus sains Irradiés, Fontenay-aux-Roses, France. 2. Inserm U1030, Radiotherapie experimentale, Institut Gustave Roussy, Villejuif, France; Laboratoire de Radio-Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. 3. Institut de Radioprotection et de Sûreté Nucléaire, PRP-HOM, SRBE, Laboratoire de Recherche sur la Régénération des tissus sains Irradiés, Fontenay-aux-Roses, France; Inserm U1030, Radiotherapie experimentale, Institut Gustave Roussy, Villejuif, France. 4. Institut Curie, Translational Research Department, Hopital St Louis, Paris, France. 5. Laboratoire de Radio-Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Service Commun d'Expérimentation Animale, Institut Gustave Roussy, Villejuif, France. 6. Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, Institut de Recherche Clinique Animale, Maisons-Alfort Cedex, France. 7. Stéphane FOUQUET, Centre de Recherche Institut de la Vision, UMR_S968 Inserm/UPMC/CHNO des Quinze-Vingts, Paris, France. 8. CNRS, UMR-8122, Institut Gustave Roussy, Villejuif, France. 9. Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMR S 872, France; INSERM, U 872, Paris, France; Université Paris Descartes-Paris 5, UMR S 872, France. 10. Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMR S 872, France; INSERM, U 872, Paris, France; Université Paris Descartes-Paris 5, UMR S 872, France; Ecole Pratique des Hautes Etudes, Laboratoire de Pharmacologie Cellulaire et Moléculaire, Paris, France. 11. Inserm U1030, Radiotherapie experimentale, Institut Gustave Roussy, Villejuif, France. 12. Institut de Radioprotection et de Sûreté Nucléaire, PRP-HOM, Fontenay-aux-Roses, France.
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 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.
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.