title: The anti-helminthic niclosamide inhibits Wnt/Frizzled1 signaling.
abstract: Wnt proteins bind to seven-transmembrane Frizzled receptors to mediate the important developmental, morphogenetic, and stem cell related tissue-regenerative effects of Wnt signaling. Dysregulated Wnt signaling is associated with many cancers. Currently, there are 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, downregulates Dishevelled-2 protein, and inhibits Wnt3A-stimulated beta-catenin stabilization and LEF/TCF reporter activity. Additionally, following niclosamide-mediated internalization, the Frizzled1 receptor colocalizes in vesicles containing transferrin and agonist-activated beta(2)-adrenergic receptor. Therefore, niclosamide may serve as a negative modulator of Wnt/Frizzled1 signaling by depleting upstream signaling molecules (i.e., Frizzled and Dishevelled) and moreover may provide a valuable means of studying the physiological consequences of Wnt signaling.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Minyong
authors.initials: M
authors.lastname: Chen
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Wang
authors.forename: Jiuyi
authors.initials: J
authors.lastname: Lu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Bond
authors.forename: Xiu-Rong
authors.initials: XR
authors.lastname: Ren
authors.forename: H Kim
authors.initials: HK
authors.lastname: Lyerly
authors.forename: Larry S
authors.initials: LS
authors.lastname: Barak
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
mesh_terms: D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000187:drug effects; D051157:Frizzled Receptors / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D018613:Microscopy, Confocal; D009534:Niclosamide / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000969:Antinematodal Agents; D051157:Frizzled Receptors; D051153:Wnt Proteins; D051176:beta Catenin; D049452:Green Fluorescent Proteins; D009534:Niclosamide