Niclosamide Suppresses Cancer Cell Growth By Inducing Wnt Co-Receptor LRP6 Degradation and Inhibiting the Wnt/β-Catenin Pathway

Hdl Handle:
http://hdl.handle.net/10675.2/688
Title:
Niclosamide Suppresses Cancer Cell Growth By Inducing Wnt Co-Receptor LRP6 Degradation and Inhibiting the Wnt/β-Catenin Pathway
Authors:
Lu, Wenyan; Lin, Cuihong; Roberts, Michael J.; Waud, William R.; Piazza, Gary A.; Li, Yonghe
Abstract:
The Wnt/b-catenin signaling pathway is important for tumor initiation and progression. The low density lipoprotein receptor-related protein-6 (LRP6) is an essential Wnt co-receptor for Wnt/b-catenin signaling and represents a promising anticancer target. Recently, the antihelminthic drug, niclosamide was found to inhibit Wnt/b-catenin signaling, although the mechanism was not well defined. We found that niclosamide was able to suppress LRP6 expression and phosphorylation, block Wnt3A-induced b-catenin accumulation, and inhibit Wnt/b-catenin signaling in HEK293 cells. Furthermore, the inhibitory effects of niclosamide on LRP6 expression/phosphorylation and Wnt/b-catenin signaling were conformed in human prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. Moreover, we showed that the mechanism by which niclosamide suppressed LRP6 resulted from increased degradation as evident by a shorter half-life. Finally, we demonstrated that niclosamide was able to induce cancer cell apoptosis, and displayed excellent anticancer activity with IC50 values less than 1 mM for prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. The IC50 values are comparable to those shown to suppress the activities of Wnt/b-catenin signaling in prostate and breast cancer cells. Our data indicate that niclosamide is a unique small molecule Wnt/b-catenin signaling inhibitor targeting the Wnt co-receptor LRP6 on the cell surface, and that niclosamide has a potential to be developed a novel chemopreventive or therapeutic agent for human prostate and breast cancer.
Editors:
Mei, Lin
Citation:
PLoS One. 2011 Dec 16; 6(12):e29290
Issue Date:
16-Dec-2011
URI:
http://hdl.handle.net/10675.2/688
DOI:
10.1371/journal.pone.0029290
PubMed ID:
22195040
PubMed Central ID:
PMC3241710
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Neurology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorLu, Wenyanen_US
dc.contributor.authorLin, Cuihongen_US
dc.contributor.authorRoberts, Michael J.en_US
dc.contributor.authorWaud, William R.en_US
dc.contributor.authorPiazza, Gary A.en_US
dc.contributor.authorLi, Yongheen_US
dc.contributor.editorMei, Lin-
dc.date.accessioned2012-10-26T16:29:34Z-
dc.date.available2012-10-26T16:29:34Z-
dc.date.issued2011-12-16en_US
dc.identifier.citationPLoS One. 2011 Dec 16; 6(12):e29290en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid22195040en_US
dc.identifier.doi10.1371/journal.pone.0029290en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/688-
dc.description.abstractThe Wnt/b-catenin signaling pathway is important for tumor initiation and progression. The low density lipoprotein receptor-related protein-6 (LRP6) is an essential Wnt co-receptor for Wnt/b-catenin signaling and represents a promising anticancer target. Recently, the antihelminthic drug, niclosamide was found to inhibit Wnt/b-catenin signaling, although the mechanism was not well defined. We found that niclosamide was able to suppress LRP6 expression and phosphorylation, block Wnt3A-induced b-catenin accumulation, and inhibit Wnt/b-catenin signaling in HEK293 cells. Furthermore, the inhibitory effects of niclosamide on LRP6 expression/phosphorylation and Wnt/b-catenin signaling were conformed in human prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. Moreover, we showed that the mechanism by which niclosamide suppressed LRP6 resulted from increased degradation as evident by a shorter half-life. Finally, we demonstrated that niclosamide was able to induce cancer cell apoptosis, and displayed excellent anticancer activity with IC50 values less than 1 mM for prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. The IC50 values are comparable to those shown to suppress the activities of Wnt/b-catenin signaling in prostate and breast cancer cells. Our data indicate that niclosamide is a unique small molecule Wnt/b-catenin signaling inhibitor targeting the Wnt co-receptor LRP6 on the cell surface, and that niclosamide has a potential to be developed a novel chemopreventive or therapeutic agent for human prostate and breast cancer.en_US
dc.rightsLu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectBiochemistryen_US
dc.subjectDrug Discoveryen_US
dc.subjectSmall Moleculesen_US
dc.subjectBiotechnologyen_US
dc.subjectDrug Discoveryen_US
dc.subjectSmall Moleculesen_US
dc.subjectMolecular Cell Biologyen_US
dc.subjectSignal Transductionen_US
dc.subjectSignaling Cascadesen_US
dc.subjectWNT Signaling Cascadeen_US
dc.subjectSignaling in Cellular Processesen_US
dc.subjectBeta-Catenin Signalingen_US
dc.subjectSignaling Pathwaysen_US
dc.subjectCatenin Signal Transductionen_US
dc.subjectMedicineen_US
dc.subjectDrugs and Devicesen_US
dc.subjectDrug Research and Developmenten_US
dc.subjectDrug Discoveryen_US
dc.subjectOncologyen_US
dc.subjectBasic Cancer Researchen_US
dc.subject.meshAdaptor Proteins, Signal Transducingen_US
dc.subject.meshApoptosisen_US
dc.subject.meshBreast Neoplasmsen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCell Proliferationen_US
dc.subject.meshDrug Screening Assays, Antitumoren_US
dc.subject.meshFemaleen_US
dc.subject.meshHEK293 Cellsen_US
dc.subject.meshHumansen_US
dc.subject.meshLow Density Lipoprotein Receptor-Related Protein-6en_US
dc.subject.meshMaleen_US
dc.subject.meshNeoplasm Proteinsen_US
dc.subject.meshNeoplasmsen_US
dc.subject.meshNiclosamideen_US
dc.subject.meshPhosphoproteinsen_US
dc.subject.meshPhosphorylationen_US
dc.subject.meshProstatic Neoplasmsen_US
dc.subject.meshProteolysisen_US
dc.subject.meshWnt Proteinsen_US
dc.subject.meshWnt Signaling Pathwayen_US
dc.subject.meshWnt3A Proteinen_US
dc.subject.meshbeta Cateninen_US
dc.titleNiclosamide Suppresses Cancer Cell Growth By Inducing Wnt Co-Receptor LRP6 Degradation and Inhibiting the Wnt/β-Catenin Pathwayen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3241710en_US
dc.contributor.corporatenameDepartment of Neurology-
dc.contributor.corporatenameCollege of Graduate Studies-
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