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The Anti-Helminthic Niclosamide Inhibits Wnt/Frizzled1 Signaling†

Identifieur interne : 000633 ( Pmc/Corpus ); précédent : 000632; suivant : 000634

The Anti-Helminthic Niclosamide Inhibits Wnt/Frizzled1 Signaling†

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

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

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PMC:2801776

Le document en format XML

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<author><name sortKey="Chen, Minyong" sort="Chen, Minyong" uniqKey="Chen M" first="Minyong" last="Chen">Minyong Chen</name>
<affiliation><nlm:aff id="A1"> Department of Medicine, Duke University Medical Center, Durham, NC 27710</nlm:aff>
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<author><name sortKey="Wang, Jiangbo" sort="Wang, Jiangbo" uniqKey="Wang J" first="Jiangbo" last="Wang">Jiangbo Wang</name>
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<author><name sortKey="Lu, Jiuyi" sort="Lu, Jiuyi" uniqKey="Lu J" first="Jiuyi" last="Lu">Jiuyi Lu</name>
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<author><name sortKey="Bond, Michael C" sort="Bond, Michael C" uniqKey="Bond M" first="Michael C." last="Bond">Michael C. Bond</name>
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<author><name sortKey="Ren, Xiu Rong" sort="Ren, Xiu Rong" uniqKey="Ren X" first="Xiu-Rong" last="Ren">Xiu-Rong Ren</name>
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<author><name sortKey="Barak, Larry S" sort="Barak, Larry S" uniqKey="Barak L" first="Larry S." last="Barak">Larry S. Barak</name>
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<author><name sortKey="Chen, Wei" sort="Chen, Wei" uniqKey="Chen W" first="Wei" last="Chen">Wei Chen</name>
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<author><name sortKey="Bond, Michael C" sort="Bond, Michael C" uniqKey="Bond M" first="Michael C." last="Bond">Michael C. Bond</name>
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<author><name sortKey="Ren, Xiu Rong" sort="Ren, Xiu Rong" uniqKey="Ren X" first="Xiu-Rong" last="Ren">Xiu-Rong Ren</name>
<affiliation><nlm:aff id="A1"> Department of Medicine, Duke University Medical Center, Durham, NC 27710</nlm:aff>
</affiliation>
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<author><name sortKey="Lyerly, H Kim" sort="Lyerly, H Kim" uniqKey="Lyerly H" first="H. Kim" last="Lyerly">H. Kim Lyerly</name>
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<author><name sortKey="Barak, Larry S" sort="Barak, Larry S" uniqKey="Barak L" first="Larry S." last="Barak">Larry S. Barak</name>
<affiliation><nlm:aff id="A3"> Department of Cell Biology, Duke University Medical Center, Durham, NC 27710</nlm:aff>
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<author><name sortKey="Chen, Wei" sort="Chen, Wei" uniqKey="Chen W" first="Wei" last="Chen">Wei Chen</name>
<affiliation><nlm:aff id="A1"> Department of Medicine, Duke University Medical Center, Durham, NC 27710</nlm:aff>
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<series><title level="j">Biochemistry</title>
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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>
</div>
</front>
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  <pmc-dir>properties manuscript</pmc-dir>
  <front><journal-meta><journal-id journal-id-type="nlm-journal-id">0370623</journal-id>
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<journal-id journal-id-type="nlm-ta">Biochemistry</journal-id>
<journal-title>Biochemistry</journal-title>
<issn pub-type="ppub">0006-2960</issn>
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<article-id pub-id-type="manuscript">NIHMS152011</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
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<title-group><article-title>The Anti-Helminthic Niclosamide Inhibits Wnt/Frizzled1 Signaling<xref rid="FN2" ref-type="fn">†</xref>
</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Minyong</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Jiangbo</given-names>
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<xref rid="A1" ref-type="aff">1</xref>
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<contrib contrib-type="author"><name><surname>Lu</surname>
<given-names>Jiuyi</given-names>
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<contrib contrib-type="author"><name><surname>Bond</surname>
<given-names>Michael C.</given-names>
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<xref rid="A1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ren</surname>
<given-names>Xiu-Rong</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lyerly</surname>
<given-names>H. Kim</given-names>
</name>
<xref rid="A2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Barak</surname>
<given-names>Larry S.</given-names>
</name>
<xref rid="A3" ref-type="aff">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Wei</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
<xref rid="FN1" ref-type="author-notes">*</xref>
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<aff id="A1"><label>1</label>
 Department of Medicine, Duke University Medical Center, Durham, NC 27710</aff>
<aff id="A2"><label>2</label>
 Department of Surgery, Duke University Medical Center, Durham, NC 27710</aff>
<aff id="A3"><label>3</label>
 Department of Cell Biology, Duke University Medical Center, Durham, NC 27710</aff>
<author-notes><corresp id="FN1"><label>*</label>
Corresponding author. Department of Medicine, Division of Gastroenterology, Duke University, Durham, NC 27710. Phone: (919) 684-4433. Fax: (919) 684-4183. <email>w.chen@duke.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>24</day>
<month>11</month>
<year>2009</year>
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<pub-date pub-type="ppub"><day>3</day>
<month>11</month>
<year>2009</year>
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<pub-date pub-type="pmc-release"><day>3</day>
<month>11</month>
<year>2010</year>
</pub-date>
<volume>48</volume>
<issue>43</issue>
<fpage>10267</fpage>
<lpage>10274</lpage>
<abstract><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>
</abstract>
<kwd-group><kwd>β-Catenin</kwd>
<kwd>Dishevelled-2</kwd>
<kwd>Frizzled1</kwd>
<kwd>LEF/TCF</kwd>
<kwd>Niclosamide</kwd>
<kwd>Receptor internalization</kwd>
<kwd>and Wnt signaling</kwd>
</kwd-group>
<contract-num rid="CA1">R01 CA113656-03
				||CA</contract-num>
<contract-sponsor id="CA1">National Cancer Institute : NCI</contract-sponsor>
</article-meta>
</front>
</pmc>
</record>

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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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