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Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor

Wilms tumor (WT) is the most common renal malignancy in children and the fourth most common pediatric solid malignancy in the US. Although the mechanisms underlying the WT biology are complex, these tumors most often demonstrate activation of the canonical Wnt/β-catenin pathway. We and others have s...

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Autores principales: Polosukhina, Dina, Love, Harold D., Moses, Harold L., Lee, Ethan, Zent, Roy, Clark, Peter E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cognizant Communication Corporation 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670010/
https://www.ncbi.nlm.nih.gov/pubmed/28695795
http://dx.doi.org/10.3727/096504017X14992942781895
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author Polosukhina, Dina
Love, Harold D.
Moses, Harold L.
Lee, Ethan
Zent, Roy
Clark, Peter E.
author_facet Polosukhina, Dina
Love, Harold D.
Moses, Harold L.
Lee, Ethan
Zent, Roy
Clark, Peter E.
author_sort Polosukhina, Dina
collection PubMed
description Wilms tumor (WT) is the most common renal malignancy in children and the fourth most common pediatric solid malignancy in the US. Although the mechanisms underlying the WT biology are complex, these tumors most often demonstrate activation of the canonical Wnt/β-catenin pathway. We and others have shown that constitutive activation of β-catenin restricted to the renal epithelium is sufficient to induce primitive renal epithelial tumors, which resemble human WT. Here we demonstrate that pharmacologic inhibition of β-catenin gene transcription with pyrvinium inhibits tumor growth and metastatic progression in a murine model of WT. Cellular invasion is significantly inhibited in both murine WT-like and human WT cells and is accompanied by downregulation of the oncogenes Myc and Birc5 (survivin). Our studies provide proof of the concept that the canonical Wnt/β-catenin pathway may be a novel therapeutic target in the management of WT.
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spelling pubmed-56700102017-11-03 Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor Polosukhina, Dina Love, Harold D. Moses, Harold L. Lee, Ethan Zent, Roy Clark, Peter E. Oncol Res Article Wilms tumor (WT) is the most common renal malignancy in children and the fourth most common pediatric solid malignancy in the US. Although the mechanisms underlying the WT biology are complex, these tumors most often demonstrate activation of the canonical Wnt/β-catenin pathway. We and others have shown that constitutive activation of β-catenin restricted to the renal epithelium is sufficient to induce primitive renal epithelial tumors, which resemble human WT. Here we demonstrate that pharmacologic inhibition of β-catenin gene transcription with pyrvinium inhibits tumor growth and metastatic progression in a murine model of WT. Cellular invasion is significantly inhibited in both murine WT-like and human WT cells and is accompanied by downregulation of the oncogenes Myc and Birc5 (survivin). Our studies provide proof of the concept that the canonical Wnt/β-catenin pathway may be a novel therapeutic target in the management of WT. Cognizant Communication Corporation 2017-11-02 /pmc/articles/PMC5670010/ /pubmed/28695795 http://dx.doi.org/10.3727/096504017X14992942781895 Text en Copyright © 2017 Cognizant, LLC. http://creativecommons.org/licenses/by-nc-nd/4.0/ This article is licensed under a Creative Commons Attribution-NonCommercial NoDerivatives 4.0 International License.
spellingShingle Article
Polosukhina, Dina
Love, Harold D.
Moses, Harold L.
Lee, Ethan
Zent, Roy
Clark, Peter E.
Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor
title Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor
title_full Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor
title_fullStr Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor
title_full_unstemmed Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor
title_short Pharmacologic Inhibition of β-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor
title_sort pharmacologic inhibition of β-catenin with pyrvinium inhibits murine and human models of wilms tumor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670010/
https://www.ncbi.nlm.nih.gov/pubmed/28695795
http://dx.doi.org/10.3727/096504017X14992942781895
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