Aurora A and NF-κB Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA.
Cancer Res
; 77(2): 494-508, 2017 01 15.
Article
em En
| MEDLINE
| ID: mdl-28069801
ABSTRACT
Aurora A-dependent NF-κB signaling portends poor prognosis in acute myeloid leukemia (AML) and other cancers, but the functional basis underlying this association is unclear. Here, we report that Aurora A is essential for Thr9 phosphorylation of the TRAF-interacting protein TIFA, triggering activation of the NF-κB survival pathway in AML. TIFA protein was overexpressed concurrently with Aurora A and NF-κB signaling factors in patients with de novo AML relative to healthy individuals and also correlated with poor prognosis. Silencing TIFA in AML lines and primary patient cells decreased leukemic cell growth and chemoresistance via downregulation of prosurvival factors Bcl-2 and Bcl-XL that support NF-κB-dependent antiapoptotic events. Inhibiting TIFA perturbed leukemic cytokine secretion and reduced the IC50 of chemotherapeutic drug treatments in AML cells. Furthermore, in vivo delivery of TIFA-inhibitory fragments potentiated the clearance of myeloblasts in the bone marrow of xenograft-recipient mice via enhanced chemotoxicity. Collectively, our results showed that TIFA supports AML progression and that its targeting can enhance the efficacy of AML treatments. Cancer Res; 77(2); 494-508. ©2016 AACR.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
/
NF-kappa B
/
Resistencia a Medicamentos Antineoplásicos
/
Proteínas Adaptadoras de Transdução de Sinal
/
Aurora Quinase A
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Taiwan