PrP(c) deficiency and dasatinib protect mouse intestines against radiation injury by inhibiting of c-Src.
Radiother Oncol
; 120(1): 175-83, 2016 07.
Article
en En
| MEDLINE
| ID: mdl-27406443
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Traumatismos por Radiación
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Familia-src Quinasas
/
Dasatinib
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Proteínas Priónicas
/
Intestinos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Radiother Oncol
Año:
2016
Tipo del documento:
Article
País de afiliación:
Francia