Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia.
Cancer Cell
; 24(6): 766-76, 2013 Dec 09.
Article
em En
| MEDLINE
| ID: mdl-24291004
ABSTRACT
Glucocorticoid resistance is a major driver of therapeutic failure in T cell acute lymphoblastic leukemia (T-ALL). Here, we identify the AKT1 kinase as a major negative regulator of the NR3C1 glucocorticoid receptor protein activity driving glucocorticoid resistance in T-ALL. Mechanistically, AKT1 impairs glucocorticoid-induced gene expression by direct phosphorylation of NR3C1 at position S134 and blocking glucocorticoid-induced NR3C1 translocation to the nucleus. Moreover, we demonstrate that loss of PTEN and consequent AKT1 activation can effectively block glucocorticoid-induced apoptosis and induce resistance to glucocorticoid therapy. Conversely, pharmacologic inhibition of AKT with MK2206 effectively restores glucocorticoid-induced NR3C1 translocation to the nucleus, increases the response of T-ALL cells to glucocorticoid therapy, and effectively reverses glucocorticoid resistance in vitro and in vivo.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dexametasona
/
Proteínas Proto-Oncogênicas c-akt
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Leucemia-Linfoma Linfoblástico de Células T Precursoras
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Compostos Heterocíclicos com 3 Anéis
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cancer Cell
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos