Pharmacological blockage of transforming growth factor-ß signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846.
Br J Cancer
; 124(1): 228-236, 2021 01.
Article
en En
| MEDLINE
| ID: mdl-33244122
ABSTRACT
BACKGROUND:
Metastasis is the primary cause of death in cancer patients, and its management is still a major challenge. Epithelial to mesenchymal transition (EMT) has been implicated in the process of cancer metastasis, and its pharmacological interference holds therapeutic promise.METHODS:
Traf2- and Nck-interacting kinase (TNIK) functions as a transcriptional coregulator of Wnt target genes. Given the convergence of Wnt and transforming growth factor-ß (TGFß) signalling, we examined the effects of a small-molecule TNIK inhibitor (named NCB-0846) on the TGFß1-induced EMT of lung cancer cells.RESULTS:
NCB-0846 inhibited the TGFß1-induced EMT of A549 cells. This inhibition was associated with inhibition of Sma- and Mad-Related Protein-2/3 (SMAD2/3) phosphorylation and nuclear translocation. NCB-0846 abolished the lung metastasis of TGFß1-treated A549 cells injected into the tail veins of immunodeficient mice. The inhibition of EMT was mediated by suppression of the TGFß receptor type-I (TGFBR1) gene, at least partly through the induction of microRNAs targeting the TGFBR1 transcript [miR-320 (a, b and d) and miR-186].CONCLUSIONS:
NCB-0846 pharmacologically blocks the TGFß/SMAD signalling and EMT induction of lung cancer cells by transcriptionally downregulating TGFBRI expression, representing a potentially promising approach for prevention of metastasis in lung cancer patients.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_other_respiratory_diseases
/
6_trachea_bronchus_lung_cancer
Asunto principal:
Proteínas Serina-Treonina Quinasas
/
Inhibidores de Proteínas Quinasas
/
Factor de Crecimiento Transformador beta1
/
Transición Epitelial-Mesenquimal
/
Neoplasias Pulmonares
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Br J Cancer
Año:
2021
Tipo del documento:
Article
País de afiliación:
Japón