Dickkopf-1 Inhibition Reactivates Wnt/beta-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo

The Wnt/β-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/β-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most st...

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Autores: Giralt, Irina, Gallo Oller, Gabriel, Navarro, Natalia, Zarzosa, Patricia, Pons, Guillem, Magdaleno, Ainara, Segura, Miguel F., Sabado, Constantino, Hladun, Raquel, Arango, Diego, Sánchez de Toledo, José, Moreno, Lucas, Gallego, Soledad, Roma, Josep
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universitat de Lleida (UdL)
Repositorio:Repositori Obert UdL
OAI Identifier:oai:repositori.udl.cat:10459.1/73115
Acceso en línea:https://doi.org/10.3390/ijms222312921
http://hdl.handle.net/10459.1/73115
Access Level:acceso abierto
Palabra clave:Wnt antagonists
Dickkopf proteins
DKK
β-catenin
Wnt pathway
Rhabdomyosarcoma
Differentiation
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spelling Dickkopf-1 Inhibition Reactivates Wnt/beta-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In VivoGiralt, IrinaGallo Oller, GabrielNavarro, NataliaZarzosa, PatriciaPons, GuillemMagdaleno, AinaraSegura, Miguel F.Sabado, ConstantinoHladun, RaquelArango, DiegoSánchez de Toledo, JoséMoreno, LucasGallego, SoledadRoma, JosepWnt antagonistsDickkopf proteinsDKKβ-cateninWnt pathwayRhabdomyosarcomaDifferentiationThe Wnt/β-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/β-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most studied member of the DKK family. Although the therapeutic potential of DKK-1 inhibition has been evaluated in several diseases and malignancies, little is known in pediatric tumors. Only a few works have studied the genetic inhibition and function of DKK-1 in rhabdomyosarcoma. Here, for the first time, we report the analysis of the therapeutic potential of DKK-1 pharmaceutical inhibition in rhabdomyosarcoma, the most common soft tissue sarcoma in children. We performed DKK-1 inhibition via shRNA technology and via the chemical inhibitor WAY-2626211. Its inhibition led to β-catenin activation and the modulation of focal adhesion kinase (FAK), with positive effects on in vitro expression of myogenic markers and a reduction in proliferation and invasion. In addition, WAY-262611 was able to impair survival of tumor cells in vivo. Therefore, DKK-1 could constitute a molecular target, which could lead to novel therapeutic strategies in RMS, especially in those patients with high DKK-1 expression.MDPI2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.3390/ijms222312921http://hdl.handle.net/10459.1/73115reponame:Repositori Obert UdL instname:Universitat de Lleida (UdL)InglésReproducció del document publicat a: https://doi.org/10.3390/ijms222312921International Journal of Molecular Sciences, 2021, vol. 22, mún. 23, p. 1-13cc-by (c) authors, 2021info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/oai:repositori.udl.cat:10459.1/731152026-06-24T12:42:17Z
dc.title.none.fl_str_mv Dickkopf-1 Inhibition Reactivates Wnt/beta-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo
title Dickkopf-1 Inhibition Reactivates Wnt/beta-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo
spellingShingle Dickkopf-1 Inhibition Reactivates Wnt/beta-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo
Giralt, Irina
Wnt antagonists
Dickkopf proteins
DKK
β-catenin
Wnt pathway
Rhabdomyosarcoma
Differentiation
title_short Dickkopf-1 Inhibition Reactivates Wnt/beta-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo
title_full Dickkopf-1 Inhibition Reactivates Wnt/beta-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo
title_fullStr Dickkopf-1 Inhibition Reactivates Wnt/beta-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo
title_full_unstemmed Dickkopf-1 Inhibition Reactivates Wnt/beta-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo
title_sort Dickkopf-1 Inhibition Reactivates Wnt/beta-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo
dc.creator.none.fl_str_mv Giralt, Irina
Gallo Oller, Gabriel
Navarro, Natalia
Zarzosa, Patricia
Pons, Guillem
Magdaleno, Ainara
Segura, Miguel F.
Sabado, Constantino
Hladun, Raquel
Arango, Diego
Sánchez de Toledo, José
Moreno, Lucas
Gallego, Soledad
Roma, Josep
author Giralt, Irina
author_facet Giralt, Irina
Gallo Oller, Gabriel
Navarro, Natalia
Zarzosa, Patricia
Pons, Guillem
Magdaleno, Ainara
Segura, Miguel F.
Sabado, Constantino
Hladun, Raquel
Arango, Diego
Sánchez de Toledo, José
Moreno, Lucas
Gallego, Soledad
Roma, Josep
author_role author
author2 Gallo Oller, Gabriel
Navarro, Natalia
Zarzosa, Patricia
Pons, Guillem
Magdaleno, Ainara
Segura, Miguel F.
Sabado, Constantino
Hladun, Raquel
Arango, Diego
Sánchez de Toledo, José
Moreno, Lucas
Gallego, Soledad
Roma, Josep
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Wnt antagonists
Dickkopf proteins
DKK
β-catenin
Wnt pathway
Rhabdomyosarcoma
Differentiation
topic Wnt antagonists
Dickkopf proteins
DKK
β-catenin
Wnt pathway
Rhabdomyosarcoma
Differentiation
description The Wnt/β-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/β-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most studied member of the DKK family. Although the therapeutic potential of DKK-1 inhibition has been evaluated in several diseases and malignancies, little is known in pediatric tumors. Only a few works have studied the genetic inhibition and function of DKK-1 in rhabdomyosarcoma. Here, for the first time, we report the analysis of the therapeutic potential of DKK-1 pharmaceutical inhibition in rhabdomyosarcoma, the most common soft tissue sarcoma in children. We performed DKK-1 inhibition via shRNA technology and via the chemical inhibitor WAY-2626211. Its inhibition led to β-catenin activation and the modulation of focal adhesion kinase (FAK), with positive effects on in vitro expression of myogenic markers and a reduction in proliferation and invasion. In addition, WAY-262611 was able to impair survival of tumor cells in vivo. Therefore, DKK-1 could constitute a molecular target, which could lead to novel therapeutic strategies in RMS, especially in those patients with high DKK-1 expression.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.3390/ijms222312921
http://hdl.handle.net/10459.1/73115
url https://doi.org/10.3390/ijms222312921
http://hdl.handle.net/10459.1/73115
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/ijms222312921
International Journal of Molecular Sciences, 2021, vol. 22, mún. 23, p. 1-13
dc.rights.none.fl_str_mv cc-by (c) authors, 2021
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
rights_invalid_str_mv cc-by (c) authors, 2021
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Repositori Obert UdL
instname:Universitat de Lleida (UdL)
instname_str Universitat de Lleida (UdL)
reponame_str Repositori Obert UdL
collection Repositori Obert UdL
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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