Dickkopf-1 Inhibition Reactivates Wnt/β-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo
Giralt, Irina (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Gallo-Oller, Gabriel (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Navarro Barea, Natalia (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Zarzosa, Patricia (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Pons, Guillem (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Magdaleno, Ainara (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Segura, Miguel F. (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Sábado, Constantino (Hospital Universitari Vall d'Hebron)
Hladun, Raquel (Hospital Universitari Vall d'Hebron)
Arango, Diego (Institut de Recerca Biomèdica de Lleida)
Sánchez de Toledo, José (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Moreno, Lucas (Hospital Universitari Vall d'Hebron)
Gallego, Soledad (Hospital Universitari Vall d'Hebron)
Roma, Josep (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Universitat Autònoma de Barcelona

Fecha:	2021
Resumen:	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.
Ayudas:	Instituto de Salud Carlos III PI18/00398
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Β-catenin ; Dickkopf proteins ; Differentiation ; DKK ; Rhabdomyosarcoma ; Wnt antagonists ; Wnt pathway
Publicado en:	International journal of molecular sciences, Vol. 22 (november 2021) , ISSN 1422-0067

DOI: 10.3390/ijms222312921
PMID: 34884726

13 p, 3.2 MB

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