PUBLICATION
Clotrimazole inhibits the Wnt/β-catenin pathway by activating two eIF2α kinases: The heme-regulated translational inhibitor and the double-stranded RNA-induced protein kinase
- Authors
- Yonezawa, H., Ogawa, M., Katayama, S., Shimizu, Y., Omori, N., Oku, Y., Sakyo, T., Uehara, Y., Nishiya, N.
- ID
- ZDB-PUB-181022-1
- Date
- 2018
- Source
- Biochemical and Biophysical Research Communications 506(1): 183-188 (Journal)
- Registered Authors
- Nishiya, Naoyuki
- Keywords
- Antifungal azole, Drug repositioning, Wnt, eIF2α kinase, β-catenin
- MeSH Terms
-
- Animals
- Antifungal Agents
- Azoles/pharmacology
- Clotrimazole/pharmacology*
- Enzyme Activation/drug effects
- Gene Knockdown Techniques
- Humans
- Protein Biosynthesis/drug effects
- Protein Biosynthesis/genetics
- Wnt Signaling Pathway/drug effects*
- beta Catenin/drug effects
- beta Catenin/metabolism
- eIF-2 Kinase/metabolism*
- PubMed
- 30342850 Full text @ Biochem. Biophys. Res. Commun.
Citation
Yonezawa, H., Ogawa, M., Katayama, S., Shimizu, Y., Omori, N., Oku, Y., Sakyo, T., Uehara, Y., Nishiya, N. (2018) Clotrimazole inhibits the Wnt/β-catenin pathway by activating two eIF2α kinases: The heme-regulated translational inhibitor and the double-stranded RNA-induced protein kinase. Biochemical and Biophysical Research Communications. 506(1):183-188.
Abstract
The Wnt/β-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/β-catenin signaling inhibitors. Here we show the mechanism underlying the Wnt/β-catenin pathway inhibition by antifungal azoles. Clotrimazole reduced β-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/β-catenin pathway. Thus, clotrimazole inhibits the Wnt/β-catenin pathway by decreasing β-catenin protein levels through translational regulation. Antifungal azoles represent genuine candidate compounds for anticancer drugs or chemopreventive agents that reduce adenomatous polyps.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping