Clotrimazole inhibits the Wnt/ß-catenin pathway by activating two eIF2α kinases: The heme-regulated translational inhibitor and the double-stranded RNA-induced protein kinase.
Biochem Biophys Res Commun
; 506(1): 183-188, 2018 11 17.
Article
de En
| MEDLINE
| ID: mdl-30342850
ABSTRACT
The Wnt/ß-catenin signaling pathway controls cell proliferation and differentiation, and therefore, when this pathway is excessively activated, it causes tumorigenesis. Our chemical suppressor screening in zebrafish embryos identified antifungal azoles including clotrimazole, miconazole, and itraconazole, as Wnt/ß-catenin signaling inhibitors. Here we show the mechanism underlying the Wnt/ß-catenin pathway inhibition by antifungal azoles. Clotrimazole reduced ß-catenin revels in a proteasome-independent fashion. By gene knockdown of two translational regulators, heme-regulated translational inhibitor and double-stranded RNA-induced protein kinase, we show that they mediate the clotrimazole-induced inhibition of the Wnt/ß-catenin pathway. Thus, clotrimazole inhibits the Wnt/ß-catenin pathway by decreasing ß-catenin protein levels through translational regulation. Antifungal azoles represent genuine candidate compounds for anticancer drugs or chemopreventive agents that reduce adenomatous polyps.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Clotrimazole
/
EIF-2 Kinase
/
Voie de signalisation Wnt
Type d'étude:
Prognostic_studies
Limites:
Animals
/
Humans
Langue:
En
Journal:
Biochem Biophys Res Commun
Année:
2018
Type de document:
Article
Pays d'affiliation:
Japon