Temporal DNA-PK activation drives genomic instability and therapy resistance in glioma stem cells.
JCI Insight
; 3(3)2018 02 08.
Article
en En
| MEDLINE
| ID: mdl-29415883
ABSTRACT
Cancer stem cells (CSCs) - known to be resistant to genotoxic radiation and chemotherapy - are fundamental to therapy failure and cancer relapse. Here, we reveal that glioma CSCs are hypersensitive to radiation, but a temporal DNA repair mechanism converts the intrinsic sensitivity to genomic instability and treatment resistance. Transcriptome analysis identifies DNA-dependent protein kinase (DNA-PK) as a predominant DNA repair enzyme in CSCs. Notably, DNA-PK activity is suppressed after irradiation when ROS induce the dissociation of DNA-PKcs with Ku70/80, resulting in delayed DNA repair and radiosensitivity; subsequently, after ROS clearance, the accumulated DNA damage and robust activation of DNA-PK induce genomic instability, facilitated by Rad50-mediated cell-cycle arrest, leading to enhanced malignancy, CSC overgrowth, and radioresistance. Finally, we show a requisite in vivo role for DNA-PK in CSC-mediated radioresistance and glioma progression. These findings identify a time-sensitive mechanism controlling CSC resistance to DNA-damaging treatments and suggest DNA-PK/Rad50 as promising targets for CSC eradication.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tolerancia a Radiación
/
Células Madre Neoplásicas
/
Proteínas Nucleares
/
Inestabilidad Genómica
/
Proteína Quinasa Activada por ADN
/
Glioma
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
JCI Insight
Año:
2018
Tipo del documento:
Article