Activation of Wnt/ß-catenin signaling increases apoptosis in melanoma cells treated with trail.
PLoS One
; 8(7): e69593, 2013.
Article
em En
| MEDLINE
| ID: mdl-23869245
ABSTRACT
While the TRAIL pathway represents a promising therapeutic target in melanoma, resistance to TRAIL-mediated apoptosis remains a barrier to its successful adoption. Since the Wnt/ß-catenin pathway has been implicated in facilitating melanoma cell apoptosis, we investigated the effect of Wnt/ß-catenin signaling on regulating the responses of melanoma cells to TRAIL. Co-treatment of melanoma cell lines with WNT3A-conditioned media and recombinant TRAIL significantly enhanced apoptosis compared to treatment with TRAIL alone. This apoptosis correlates with increased abundance of the pro-apoptotic proteins BCL2L11 and BBC3, and with decreased abundance of the anti-apoptotic regulator Mcl1. We then confirmed the involvement of the Wnt/ß-catenin signaling pathway by demonstrating that siRNA-mediated knockdown of an intracellular ß-catenin antagonist, AXIN1, or treating cells with an inhibitor of GSK-3 also enhanced melanoma cell sensitivity to TRAIL. These studies describe a novel regulation of TRAIL sensitivity in melanoma by Wnt/ß-catenin signaling, and suggest that strategies to enhance Wnt/ß-catenin signaling in combination with TRAIL agonists warrant further investigation.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Apoptose
/
Beta Catenina
/
Ligante Indutor de Apoptose Relacionado a TNF
/
Proteína Wnt3A
/
Via de Sinalização Wnt
/
Melanoma
Limite:
Humans
Idioma:
En
Revista:
PLoS One
Assunto da revista:
CIENCIA
/
MEDICINA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos