Doxycycline directly targets PAR1 to suppress tumor progression.
Oncotarget
; 8(10): 16829-16842, 2017 Mar 07.
Article
en En
| MEDLINE
| ID: mdl-28187433
ABSTRACT
Doxycycline have been reported to exert anti-cancer activity and have been assessed as anti-cancer agents in clinical trials. However, the direct targets of doxycycline in cancer cells remain unclear. In this study, we used a chemical proteomics approach to identify the Protease-activated receptor 1 (PAR1) as a specific target of inhibition of doxycycline. Binding assays and single-molecule imaging assays were performed to confirm the inhibition of doxycycline to PAR1. The effect of doxycycline on multi-omics and cell functions were assessed based on a PAR1/thrombin model. Molecular docking and molecular dynamic simulations revealed that doxycycline interacts with key amino acids in PAR1. Mutation of PAR1 further confirmed the computation-based results. Moreover, doxycycline provides highly selective inhibition of PAR1 signaling in tumors in vitro and in vivo. Using pathological clinical samples co-stained for doxycycline and PAR1, it was found that doxycycline fluorescence intensity and PAR1 expression shown a clear positive correlation. Thus, doxycycline may be a useful targeted anti-cancer drug that should be further investigated in clinical trials.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Doxiciclina
/
Receptor PAR-1
Tipo de estudio:
Clinical_trials
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Oncotarget
Año:
2017
Tipo del documento:
Article
País de afiliación:
China