ß-arrestin1/YAP/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer.
Nat Commun
; 10(1): 3196, 2019 07 19.
Article
en En
| MEDLINE
| ID: mdl-31324767
ABSTRACT
The limited clinical response observed in high-grade serous ovarian cancer (HG-SOC) with high frequency of TP53 mutations (mutp53) might be related to mutp53-driven oncogenic pathway network. Here we show that ß-arrestin1 (ß-arr1), interacts with YAP, triggering its cytoplasmic-nuclear shuttling. This interaction allows ß-arr1 to recruit mutp53 to the YAP-TEAD transcriptional complex upon activation of endothelin-1 receptors (ET-1R) in patient-derived HG-SOC cells and in cell lines bearing mutp53. In parallel, ß-arr1 mediates the ET-1R-induced Trio/RhoA-dependent YAP nuclear accumulation. In the nucleus, ET-1 through ß-arr1 orchestrates the tethering of YAP and mutp53 to YAP/mutp53 target gene promoters, including EDN1 that ensures persistent signals. Treatment of patient-derived xenografts reveals synergistic antitumoral and antimetastatic effects of the dual ET-1R antagonist macitentan in combination with cisplatinum, shutting-down the ß-arr1-mediated YAP/mutp53 transcriptional programme. Furthermore, ETAR/ß-arr1/YAP gene signature correlates with a worst prognosis in HG-SOC. These findings support effective combinatorial treatment for repurposing the ET-1R antagonists in HG-SOC.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Ováricas
/
Factores de Transcripción
/
Transducción de Señal
/
Proteína p53 Supresora de Tumor
/
Cistadenocarcinoma Seroso
/
Receptor de Endotelina A
/
Proteínas Adaptadoras Transductoras de Señales
/
Beta-Arrestina 1
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Nat Commun
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Italia