Tumor resistance to radiotherapy is triggered by an ATM/TAK1-dependent-increased expression of the cellular prion protein.
Oncogene
; 40(19): 3460-3469, 2021 05.
Article
en En
| MEDLINE
| ID: mdl-33767435
ABSTRACT
In solid cancers, high expression of the cellular prion protein (PrPC) is associated with stemness, invasiveness, and resistance to chemotherapy, but the role of PrPC in tumor response to radiotherapy is unknown. Here, we show that, in neuroblastoma, breast, and colorectal cancer cell lines, PrPC expression is increased after ionizing radiation (IR) and that PrPC deficiency increases radiation sensitivity and decreases radiation-induced radioresistance in tumor cells. In neuroblastoma cells, IR activates ATM that triggers TAK1-dependent phosphorylation of JNK and subsequent activation of the AP-1 transcription factor that ultimately increases PRNP promoter transcriptional activity through an AP-1 binding site in the PRNP promoter. Importantly, we show that this ATM-TAK1-PrPC pathway mediated radioresistance is activated in all tumor cell lines studied and that pharmacological inhibition of TAK1 activity recapitulates the effects of PrPC deficiency. Altogether, these results unveil how tumor cells activate PRNP to acquire resistance to radiotherapy and might have implications for therapeutic targeting of solid tumors radioresistance.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas PrPC
/
Quinasas Quinasa Quinasa PAM
/
Proteínas de la Ataxia Telangiectasia Mutada
/
Neoplasias
Límite:
Humans
Idioma:
En
Revista:
Oncogene
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Año:
2021
Tipo del documento:
Article
País de afiliación:
Francia