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The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines

Wnt/β-catenin is a major regulator of stem cell self-renewal and differentiation and this signaling pathway is aberrantly activated in a several cancers, including osteosarcoma (OS). Attenuation of Wnt/β-catenin activity by tankyrase inhibitors is an appealing strategy in treatment of OS. The effica...

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Autores principales: Wessel Stratford, Eva, Daffinrud, Jeanette, Munthe, Else, Castro, Russell, Waaler, Jo, Krauss, Stefan, Myklebost, Ola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons Ltd. 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930388/
https://www.ncbi.nlm.nih.gov/pubmed/24403055
http://dx.doi.org/10.1002/cam4.170
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author Wessel Stratford, Eva
Daffinrud, Jeanette
Munthe, Else
Castro, Russell
Waaler, Jo
Krauss, Stefan
Myklebost, Ola
author_facet Wessel Stratford, Eva
Daffinrud, Jeanette
Munthe, Else
Castro, Russell
Waaler, Jo
Krauss, Stefan
Myklebost, Ola
author_sort Wessel Stratford, Eva
collection PubMed
description Wnt/β-catenin is a major regulator of stem cell self-renewal and differentiation and this signaling pathway is aberrantly activated in a several cancers, including osteosarcoma (OS). Attenuation of Wnt/β-catenin activity by tankyrase inhibitors is an appealing strategy in treatment of OS. The efficacy of the tankyrase inhibitor JW74 was evaluated in three OS cell lines (KPD, U2OS, and SaOS-2) both at the molecular and functional level. At the molecular level, JW74 induces stabilization of AXIN2, a key component of the β-catenin destruction complex, resulting in reduced levels of nuclear β-catenin. At the functional level, JW74 induces reduced cell growth in all three tested cell lines, in part due to a delay in cell cycle progression and in part due to an induction of caspase-3-mediated apoptosis. Furthermore, JW74 induces differentiation in U2OS cells, which under standard conditions are resistant to osteogenic differentiation. JW74 also enhances differentiation of OS cell lines, which do not harbor a differentiation block. Interestingly, microRNAs (miRNAs) of the let-7 family, which are known tumor suppressors and inducers of differentiation, are significantly upregulated following treatment with JW74. We demonstrate for the first time that tankyrase inhibition triggers reduced cell growth and differentiation of OS cells. This may in part be due to an induction of let-7 miRNA. The presented data open for novel therapeutic strategies in the treatment of malignant OS.
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spelling pubmed-39303882014-03-04 The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines Wessel Stratford, Eva Daffinrud, Jeanette Munthe, Else Castro, Russell Waaler, Jo Krauss, Stefan Myklebost, Ola Cancer Med Original Research Wnt/β-catenin is a major regulator of stem cell self-renewal and differentiation and this signaling pathway is aberrantly activated in a several cancers, including osteosarcoma (OS). Attenuation of Wnt/β-catenin activity by tankyrase inhibitors is an appealing strategy in treatment of OS. The efficacy of the tankyrase inhibitor JW74 was evaluated in three OS cell lines (KPD, U2OS, and SaOS-2) both at the molecular and functional level. At the molecular level, JW74 induces stabilization of AXIN2, a key component of the β-catenin destruction complex, resulting in reduced levels of nuclear β-catenin. At the functional level, JW74 induces reduced cell growth in all three tested cell lines, in part due to a delay in cell cycle progression and in part due to an induction of caspase-3-mediated apoptosis. Furthermore, JW74 induces differentiation in U2OS cells, which under standard conditions are resistant to osteogenic differentiation. JW74 also enhances differentiation of OS cell lines, which do not harbor a differentiation block. Interestingly, microRNAs (miRNAs) of the let-7 family, which are known tumor suppressors and inducers of differentiation, are significantly upregulated following treatment with JW74. We demonstrate for the first time that tankyrase inhibition triggers reduced cell growth and differentiation of OS cells. This may in part be due to an induction of let-7 miRNA. The presented data open for novel therapeutic strategies in the treatment of malignant OS. John Wiley & Sons Ltd. 2014-02 2013-12-17 /pmc/articles/PMC3930388/ /pubmed/24403055 http://dx.doi.org/10.1002/cam4.170 Text en © 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. http://creativecommons.org/licenses/by/3.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Wessel Stratford, Eva
Daffinrud, Jeanette
Munthe, Else
Castro, Russell
Waaler, Jo
Krauss, Stefan
Myklebost, Ola
The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines
title The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines
title_full The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines
title_fullStr The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines
title_full_unstemmed The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines
title_short The tankyrase-specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines
title_sort tankyrase-specific inhibitor jw74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930388/
https://www.ncbi.nlm.nih.gov/pubmed/24403055
http://dx.doi.org/10.1002/cam4.170
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