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

• Published in: International journal of molecular sciences 2021-11, Vol.22 (23), p.12921
• Main Authors: Giralt, Irina, Gallo-Oller, Gabriel, Navarro, Natalia, Zarzosa, Patricia, Pons, Guillem, Magdaleno, Ainara, Segura, Miguel F, Sábado, Constantino, Hladun, Raquel, Arango, Diego, Sánchez de Toledo, José, Moreno, Lucas, Gallego, Soledad, Roma, Josep
• Format: Article
• Language: English
• Subjects: Animals; Antagonists; beta Catenin - metabolism; Cancer; Case-Control Studies; Cell growth; Cell Line, Tumor; Deregulation; Dkk1 protein; Embryogenesis; Focal adhesion kinase; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Gene expression; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Kinases; Markers; Mice; Mice, SCID; Molecular Targeted Therapy; Muscles - metabolism; MyoD Protein - metabolism; Myogenin - metabolism; Naphthalenes - pharmacology; Naphthalenes - therapeutic use; Pediatrics; Piperidines - pharmacology; Piperidines - therapeutic use; Proteins; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rhabdomyosarcoma; Rhabdomyosarcoma - drug therapy; Rhabdomyosarcoma - etiology; Rhabdomyosarcoma - metabolism; RNA, Small Interfering - therapeutic use; Signal transduction; Soft tissue sarcoma; Soft tissues; Survival; Tumor cells; Tumors; Wnt protein; Wnt Signaling Pathway - drug effects; Xenograft Model Antitumor Assays; β-Catenin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222312921

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.