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

Abstract

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.

• Authors: Irina Giralt, Gabriel Gallo-Oller, Natalia Navarro, Patricia Zarzosa, Guillem Pons, Ainara Magdaleno, Miguel F Segura, Constantino Sábado, Raquel Hladun, Diego Arango, José Sánchez de Toledo, Lucas Moreno, Soledad Gallego, Josep Roma
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 23 (Nov 29 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34884726 (Publication Type: Journal Article)

Chemical References

• DKK1 protein, human
• Dkk1 protein, mouse
• Intercellular Signaling Peptides and Proteins
• MyoD Protein
• MyoD1 myogenic differentiation protein
• Myogenin
• Naphthalenes
• Piperidines
• Pyrimidines
• RNA, Small Interfering
• WAY-262611
• beta Catenin
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• Animals
• Case-Control Studies
• Cell Line, Tumor
• Focal Adhesion Protein-Tyrosine Kinases (metabolism)
• Humans
• Intercellular Signaling Peptides and Proteins (metabolism)
• Mice, SCID
• Molecular Targeted Therapy
• Muscles (metabolism)
• MyoD Protein (metabolism)
• Myogenin (metabolism)
• Naphthalenes (pharmacology, therapeutic use)
• Piperidines (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• RNA, Small Interfering (therapeutic use)
• Rhabdomyosarcoma (drug therapy, etiology, metabolism)
• Wnt Signaling Pathway (drug effects)
• Xenograft Model Antitumor Assays
• beta Catenin (metabolism)