Canonical WNT/β-Catenin Signaling Plays a Subordinate Role in Rhabdomyosarcomas

Ragab, Nada; Viehweger, Florian; Bauer, Julia; Geyer, Natalie; Yang, Mingya; Seils, Anna; Belharazem, Djeda; Brembeck, Felix H.; Schildhaus, Hans–Ulrich; Marx, Alexander; Hahn, Heidi; Simon-Keller, Katja

doi:10.3389/fped.2018.00378

Cited by 6 publications

(10 citation statements)

References 57 publications

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“…In our work on RMS, the observed increase in β-catenin expression and the promotion of its nuclear location, both observed after genetic or pharmacological DKK-1 inhibition, did not produce significant variations in the canonical target c-Myc. This result is in agreement with previous observations that point out a relevance of the non-canonical Wnt signaling pathway in RMS [ 23 , 24 ]. However, the consistent activation of myogenic markers such as MYOD1 and myogenin, together with the reduction of FAK expression, suggests the triggering of a coordinated anti-oncogenic response.…”

Section: Discussionsupporting

confidence: 94%

“…Despite the effects on proliferation and myogenic markers observed in vitro, genetic inhibition or treatment with WAY-262611 did not produce significant effects on tumor growth in the primary mouse models. These results coincide with a previous work where they show that reactivation of the β-catenin pathway did not produce significant effects on proliferation in a RMS in vivo model [ 23 ]. Indeed, it has been described that activation of Wnt/β-catenin signaling produces differentiation of RMS cells without a clear effect in proliferation and/or apoptosis [ 24 ].…”

Section: Discussionsupporting

confidence: 93%

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

Giralt

Gallo-Oller

Navarro

et al. 2021

IJMS

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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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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 93%

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

Giralt

Gallo-Oller

Navarro

et al. 2021

IJMS

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“…In order to verify the protective mechanism of LE, which increased Wnt1, we were required to interrupt the protective process. XAV939, a Wnt/β-catenin signaling pathway inhibitor, has been commonly utilized to inhibit Wnt activity in many studies [ 45 , 46 ]. In the present study, the i.p.…”

Section: Discussionmentioning

confidence: 99%

Lipid Emulsion Improves Functional Recovery in an Animal Model of Stroke

Tanioka

Park

et al. 2020

IJMS

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Stroke is a life-threatening condition that leads to the death of many people around the world. Reperfusion injury after ischemic stroke is a recurrent problem associated with various surgical procedures that involve the removal of blockages in the brain arteries. Lipid emulsion was recently shown to attenuate ischemic reperfusion injury in the heart and to protect the brain from excitotoxicity. However, investigations on the protective mechanisms of lipid emulsion against ischemia in the brain are still lacking. This study aimed to determine the neuroprotective effects of lipid emulsion in an in vivo rat model of ischemic reperfusion injury through middle cerebral artery occlusion (MCAO). Under sodium pentobarbital anesthesia, rats were subjected to MCAO surgery and were administered with lipid emulsion through intra-arterial injection during reperfusion. The experimental animals were assessed for neurological deficit wherein the brains were extracted at 24 h after reperfusion for triphenyltetrazolium chloride staining, immunoblotting and qPCR. Neuroprotection was found to be dosage-dependent and the rats treated with 20% lipid emulsion had significantly decreased infarction volumes and lower Bederson scores. Phosphorylation of Akt and glycogen synthase kinase 3-β (GSK3-β) were increased in the 20% lipid-emulsion treated group. The Wnt-associated signals showed a marked increase with a concomitant decrease in signals of inflammatory markers in the group treated with 20% lipid emulsion. The protective effects of lipid emulsion and survival-related expression of genes such as Akt, GSK-3β, Wnt1 and β-catenin were reversed by the intra-peritoneal administration of XAV939 through the inhibition of the Wnt/β-catenin signaling pathway. These results suggest that lipid emulsion has neuroprotective effects against ischemic reperfusion injury in the brain through the modulation of the Wnt signaling pathway and may provide potential insights for the development of therapeutic targets.

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“…In contrast, the relevance and potential for clinical intervention in the Wnt pathway in ARMS remains highly controversial [204]. So far, a single study by Annavarapu et al found an inhibition of proliferation and self-renewal capacity after pharmacological re-activation of the Wnt pathway in vitro [205].…”

Section: Wnt/β-catenin Pathwaymentioning

confidence: 99%

Targeting the undruggable: exploiting neomorphic features of fusion oncoproteins in childhood sarcomas for innovative therapies

Knott

Hölting²,

Ohmura³

et al. 2019

Cancer Metastasis Rev

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While sarcomas account for approximately 1% of malignant tumors of adults, they are particularly more common in children and adolescents affected by cancer. In contrast to malignancies that occur in later stages of life, childhood tumors, including sarcoma, are characterized by a striking paucity of somatic mutations. However, entity-defining fusion oncogenes acting as the main oncogenic driver mutations are frequently found in pediatric bone and soft-tissue sarcomas such as Ewing sarcoma (EWSR1-FLI1), alveolar rhabdomyosarcoma (PAX3/7-FOXO1), and synovial sarcoma (SS18-SSX1/2/4). Since strong oncogene-dependency has been demonstrated in these entities, direct pharmacological targeting of these fusion oncogenes has been excessively attempted, thus far, with limited success. Despite apparent challenges, our increasing understanding of the neomorphic features of these fusion oncogenes in conjunction with rapid technological advances will likely enable the development of new strategies to therapeutically exploit these neomorphic features and to ultimately turn the "undruggable" into first-line target structures. In this review, we provide a broad overview of the current literature on targeting neomorphic features of fusion oncogenes found in Ewing sarcoma, alveolar rhabdomyosarcoma, and synovial sarcoma, and give a perspective for future developments.

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Canonical WNT/β-Catenin Signaling Plays a Subordinate Role in Rhabdomyosarcomas

Cited by 6 publications

References 57 publications

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

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

Lipid Emulsion Improves Functional Recovery in an Animal Model of Stroke

Targeting the undruggable: exploiting neomorphic features of fusion oncoproteins in childhood sarcomas for innovative therapies

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