Glycogen synthase kinase 3 inhibitors induce the canonical WNT/ß-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma.
Proc Natl Acad Sci U S A
; 111(14): 5349-54, 2014 Apr 08.
Article
em En
| MEDLINE
| ID: mdl-24706870
ABSTRACT
Embryonal rhabdomyosarcoma (ERMS) is a common pediatric malignancy of muscle, with relapse being the major clinical challenge. Self-renewing tumor-propagating cells (TPCs) drive cancer relapse and are confined to a molecularly definable subset of ERMS cells. To identify drugs that suppress ERMS self-renewal and induce differentiation of TPCs, a large-scale chemical screen was completed. Glycogen synthase kinase 3 (GSK3) inhibitors were identified as potent suppressors of ERMS growth through inhibiting proliferation and inducing terminal differentiation of TPCs into myosin-expressing cells. In support of GSK3 inhibitors functioning through activation of the canonical WNT/ß-catenin pathway, recombinant WNT3A and stabilized ß-catenin also enhanced terminal differentiation of human ERMS cells. Treatment of ERMS-bearing zebrafish with GSK3 inhibitors activated the WNT/ß-catenin pathway, resulting in suppressed ERMS growth, depleted TPCs, and diminished self-renewal capacity in vivo. Activation of the canonical WNT/ß-catenin pathway also significantly reduced self-renewal of human ERMS, indicating a conserved function for this pathway in modulating ERMS self-renewal. In total, we have identified an unconventional tumor suppressive role for the canonical WNT/ß-catenin pathway in regulating self-renewal of ERMS and revealed therapeutic strategies to target differentiation of TPCs in ERMS.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Rabdomiossarcoma Embrionário
/
Quinase 3 da Glicogênio Sintase
/
Inibidores Enzimáticos
/
Beta Catenina
/
Via de Sinalização Wnt
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article