Warfarin Blocks Gas6-Mediated Axl Activation Required for Pancreatic Cancer Epithelial Plasticity and Metastasis.
Cancer Res
; 75(18): 3699-705, 2015 Sep 15.
Article
em En
| MEDLINE
| ID: mdl-26206560
ABSTRACT
Repurposing "old" drugs can facilitate rapid clinical translation but necessitates novel mechanistic insight. Warfarin, a vitamin K "antagonist" used clinically for the prevention of thrombosis for more than 50 years, has been shown to have anticancer effects. We hypothesized that the molecular mechanism underlying its antitumor activity is unrelated to its effect on coagulation, but is due to inhibition of the Axl receptor tyrosine kinase on tumor cells. Activation of Axl by its ligand Gas6, a vitamin K-dependent protein, is inhibited at doses of warfarin that do not affect coagulation. Here, we show that inhibiting Gas6-dependent Axl activation with low-dose warfarin, or with other tumor-specific Axl-targeting agents, blocks the progression and spread of pancreatic cancer. Warfarin also inhibited Axl-dependent tumor cell migration, invasiveness, and proliferation while increasing apoptosis and sensitivity to chemotherapy. We conclude that Gas6-induced Axl signaling is a critical driver of pancreatic cancer progression and its inhibition with low-dose warfarin or other Axl-targeting agents may improve outcome in patients with Axl-expressing tumors.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Prevencao_e_fatores_de_risco
/
Agentes_cancerigenos
/
Tipos_de_cancer
/
Outros_tipos
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
/
Varfarina
/
Proteínas Proto-Oncogênicas
/
Receptores Proteína Tirosina Quinases
/
Carcinoma Ductal Pancreático
/
Peptídeos e Proteínas de Sinalização Intercelular
/
Transição Epitelial-Mesenquimal
/
Proteínas de Neoplasias
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
2015
Tipo de documento:
Article