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The Anti-Helminthic Niclosamide Inhibits Wnt/Frizzled1 Signaling†

Identifieur interne : 001510 ( Main/Exploration ); précédent : 001509; suivant : 001511

The Anti-Helminthic Niclosamide Inhibits Wnt/Frizzled1 Signaling†

Auteurs : Minyong Chen [États-Unis] ; Jiangbo Wang [États-Unis] ; Jiuyi Lu [États-Unis] ; Michael C. Bond [États-Unis] ; Xiu-Rong Ren [États-Unis] ; H. Kim Lyerly [États-Unis] ; Larry S. Barak [États-Unis] ; Wei Chen [États-Unis]

Source :

Biochemistry [ 0006-2960 ] ; 2009.

RBID : PMC:2801776

Abstract

Wnt proteins bind to seven-transmembrane Frizzled receptors to mediate the important developmental, morphogenetic, and tissue-regenerative effects of Wnt signaling. Dysregulated Wnt signaling is associated with many cancers. Currently there exist no drug candidates, or even tool compounds that modulate Wnt-mediated receptor trafficking, and subsequent Wnt signaling. We examined libraries of FDA-approved drugs for their utility as Frizzled internalization modulators, employing a primary imaged-based GFP-fluorescence assay that uses Frizzled1 endocytosis as the readout. We now report that the anti-helminthic niclosamide, a drug used for the treatment of tapeworm, promotes Frizzled1 endocytosis, down regulates Dishevelled-2 protein, and inhibits Wnt3A-stimulated β-catenin stabilization and LEF/TCF reporter activity. Additionally, following niclosamide mediated internalization, the Frizzled1 receptor co-localizes in vesicles containing Transferrin and agonist-activated β₂-adrenergic receptor. Therefore, niclosamide may serve as a negative modulator of Wnt/Frizzled1 signaling by depleting up-stream signaling molecules (i.e. Frizzled and Dishevelled), and moreover may provide a valuable means to study the physiological consequences of Wnt signaling.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801776

DOI: 10.1021/bi9009677
PubMed: 19772353
PubMed Central: 2801776

Affiliations:

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<front><div type="abstract" xml:lang="en"><p id="P1">Wnt proteins bind to seven-transmembrane Frizzled receptors to mediate the important developmental, morphogenetic, and tissue-regenerative effects of Wnt signaling. Dysregulated Wnt signaling is associated with many cancers. Currently there exist no drug candidates, or even tool compounds that modulate Wnt-mediated receptor trafficking, and subsequent Wnt signaling. We examined libraries of FDA-approved drugs for their utility as Frizzled internalization modulators, employing a primary imaged-based GFP-fluorescence assay that uses Frizzled1 endocytosis as the readout. We now report that the anti-helminthic niclosamide, a drug used for the treatment of tapeworm, promotes Frizzled1 endocytosis, down regulates Dishevelled-2 protein, and inhibits Wnt3A-stimulated β-catenin stabilization and LEF/TCF reporter activity. Additionally, following niclosamide mediated internalization, the Frizzled1 receptor co-localizes in vesicles containing Transferrin and agonist-activated β<sub>2</sub>
-adrenergic receptor. Therefore, niclosamide may serve as a negative modulator of Wnt/Frizzled1 signaling by depleting up-stream signaling molecules (i.e. Frizzled and Dishevelled), and moreover may provide a valuable means to study the physiological consequences of Wnt signaling.</p>
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The Anti-Helminthic Niclosamide Inhibits Wnt/Frizzled1 Signaling†

The Anti-Helminthic Niclosamide Inhibits Wnt/Frizzled1 Signaling†

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Abstract

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