Dickkopf-1 Inhibition Reactivates Wnt/β-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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Detalles Bibliográficos
Autores: Giralt, Irina|||0000-0002-9094-4325, Gallo-Oller, Gabriel|||0000-0002-3864-1941, Navarro Barea, Natalia|||0000-0002-2160-6656, Zarzosa, Patricia|||0000-0002-9711-8384, Pons, Guillem|||0000-0001-8128-740X, Magdaleno, Ainara|||0000-0002-2718-3244, Segura, Miguel F.|||0000-0003-0916-3618, Sábado, Constantino|||0000-0003-3956-5466, Hladun, Raquel|||0000-0002-3191-1750, Arango, Diego|||0000-0003-2953-3284, Sánchez de Toledo Codina, José|||0000-0002-1034-1920, Moreno Martin Retortillo, Lucas|||0000-0002-0708-1670, Gallego, Soledad|||0000-0002-4712-9624, Roma, Josep|||0000-0001-7692-6123
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:292303
Acceso en línea:https://ddd.uab.cat/record/292303
https://dx.doi.org/urn:doi:10.3390/ijms222312921
Access Level:acceso abierto
Palabra clave:Β-catenin
Dickkopf proteins
Differentiation
DKK
Rhabdomyosarcoma
Wnt antagonists
Wnt pathway
Descripción
Sumario: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.

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