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Spiperone enhances intracellular calcium level and inhibits the Wnt signaling pathway

BACKGROUND: Wnt signaling affects fundamental development pathways by regulating cell proliferation and differentiation. Aberrant activation of Wnt/β-catenin signaling promotes the development of several cancers and is an attractive target for chemopreventive and chemotherapeutic agents. RESULTS: In...

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Detalles Bibliográficos
Autores principales: Lu, Desheng, Carson, Dennis A
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789054/
https://www.ncbi.nlm.nih.gov/pubmed/19948059
http://dx.doi.org/10.1186/1471-2210-9-13
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author Lu, Desheng
Carson, Dennis A
author_facet Lu, Desheng
Carson, Dennis A
author_sort Lu, Desheng
collection PubMed
description BACKGROUND: Wnt signaling affects fundamental development pathways by regulating cell proliferation and differentiation. Aberrant activation of Wnt/β-catenin signaling promotes the development of several cancers and is an attractive target for chemopreventive and chemotherapeutic agents. RESULTS: In order to identify the novel antagonists for the Wnt/β-catenin pathway, we employed a cell-based Wnt reporter system (TOPflash) to screen a library of 960 known drugs. We identified spiperone, a psychotropic drug, as a novel Wnt inhibitor, which specifically blocks canonical Wnt signaling prior to the activation of β-catenin. The Wnt inhibitory function of spiperone is not associated with its dopamine-, serotonin- and sigma-receptor antagonist properties. Instead, spiperone increases intracellular calcium levels in a similar manner to thapsigargin, that also impedes Wnt signal transduction. Inhibition of protein kinase C had no effect on spiperone-mediated antagonism of Wnt signaling. CONCLUSION: Spiperone is a calcium regulator. It inhibits Wnt signaling by enhancing intracellular calcium levels.
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spelling pubmed-27890542009-12-05 Spiperone enhances intracellular calcium level and inhibits the Wnt signaling pathway Lu, Desheng Carson, Dennis A BMC Pharmacol Research article BACKGROUND: Wnt signaling affects fundamental development pathways by regulating cell proliferation and differentiation. Aberrant activation of Wnt/β-catenin signaling promotes the development of several cancers and is an attractive target for chemopreventive and chemotherapeutic agents. RESULTS: In order to identify the novel antagonists for the Wnt/β-catenin pathway, we employed a cell-based Wnt reporter system (TOPflash) to screen a library of 960 known drugs. We identified spiperone, a psychotropic drug, as a novel Wnt inhibitor, which specifically blocks canonical Wnt signaling prior to the activation of β-catenin. The Wnt inhibitory function of spiperone is not associated with its dopamine-, serotonin- and sigma-receptor antagonist properties. Instead, spiperone increases intracellular calcium levels in a similar manner to thapsigargin, that also impedes Wnt signal transduction. Inhibition of protein kinase C had no effect on spiperone-mediated antagonism of Wnt signaling. CONCLUSION: Spiperone is a calcium regulator. It inhibits Wnt signaling by enhancing intracellular calcium levels. BioMed Central 2009-11-30 /pmc/articles/PMC2789054/ /pubmed/19948059 http://dx.doi.org/10.1186/1471-2210-9-13 Text en Copyright ©2009 Lu and Carson; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research article
Lu, Desheng
Carson, Dennis A
Spiperone enhances intracellular calcium level and inhibits the Wnt signaling pathway
title Spiperone enhances intracellular calcium level and inhibits the Wnt signaling pathway
title_full Spiperone enhances intracellular calcium level and inhibits the Wnt signaling pathway
title_fullStr Spiperone enhances intracellular calcium level and inhibits the Wnt signaling pathway
title_full_unstemmed Spiperone enhances intracellular calcium level and inhibits the Wnt signaling pathway
title_short Spiperone enhances intracellular calcium level and inhibits the Wnt signaling pathway
title_sort spiperone enhances intracellular calcium level and inhibits the wnt signaling pathway
topic Research article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789054/
https://www.ncbi.nlm.nih.gov/pubmed/19948059
http://dx.doi.org/10.1186/1471-2210-9-13
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