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.

Tumor suppressive functions of WNT5A in rhabdomyosarcoma

“…Therefore, at first glance, the WNT5A-induced inhibition of the WNT/β-Catenin pathway seemed to be associated with a decrease in cell proliferation and migration in both colon cancer and RMS cells. However, this is rather not the case, since a recent study showed decreased proliferation with concomitant activation of WNT/β-Catenin signaling in RMS cell lines deficient for DKK1 ( 15 ) and since we recently showed that canonical WNT signaling and β-Catenin do not affect aggressiveness of RMS cell lines or in a murine RMS model ( 17 ).…”

“…However, it has been reported that stimulation of RMS cell lines with recombinant WNT3A leads to nuclear translocation of β-Catenin and blocks cellular proliferation ( 13 , 14 ). In addition, downregulation of the main inhibitor of WNT/β-Catenin signaling Dickkopf1 leads to expression of active β-Catenin and inhibition of proliferation and invasion of RMS tumor cells ( 15 ). These results imply that activation of WNT/β-Catenin signaling has antitumoral effects in RMS.…”

O‐GlcNAcylated LARP1 positively regulated by circCLNS1A facilitates hepatoblastoma progression through DKK4/β‐catenin signalling

“… 34 Beyond the CTNNB1 mutation, the Dickkopf (DKK) family is known for fine‐tuning Wnt activity. 35 For example, DKK1 is defined as an agonist of the Wnt/β‐catenin signalling pathway in HCC 36 but an antagonist in rhabdomyosarcoma 37 and ovarian cancer. 38 Similarly, DKK4 affects tumourigenesis and development by modulating the Wnt/β‐catenin signalling pathway.…”

Wnt/β-Catenin Signaling Pathway in Pediatric Tumors: Implications for Diagnosis and Treatment

“…When DKK was inhibited, β-catenin was reactivated and focal adhesion kinase (FAK) was consequently modulated, which had a favorable impact on in vitro expression of myogenic markers and decreased the proliferation and invasion of cells. Thus, adoption of treatment modalities based on the reactivation of Wnt/β-catenin signaling, intertwined regulatory pathways shall be taken into consideration in RMS patients [ 67 ].…”