| RRC ID |
65583
|
| 著者 |
Yonezawa H, Ogawa M, Katayama S, Shimizu Y, Omori N, Oku Y, Sakyo T, Uehara Y, Nishiya N.
|
| タイトル |
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.
|
| ジャーナル |
Biochem Biophys Res Commun
|
| 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.
|
| 巻・号 |
506(1)
|
| ページ |
183-188
|
| 公開日 |
2018-11-17
|
| DOI |
10.1016/j.bbrc.2018.10.053
|
| PII |
S0006-291X(18)32199-5
|
| PMID |
30342850
|
| MeSH |
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*
|
| IF |
2.985
|
| リソース情報 |
| ゼブラフィッシュ |
RIKEN WT |
