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Pharmacologic Inhibition of Ezrin-Radixin-Moesin Phosphorylation is a Novel Therapeutic Strategy in Rhabdomyosarcoma.
This study investigates the inhibition of ERM phosphorylation using a small molecule pharmacophore NSC668394 as a potential strategy against RMS. Upon in vitro treatment with NSC668394, RMS cells exhibit a dose-dependent decrease in cell viability and proliferation, with induction of caspase-3 cleavage and apoptosis. siRNA-mediated knockdown of individual ERM protein expression revealed that each regulates RMS survival to a different degree. In vivo administration of NSC668394 in RMS xenografts causes significant decrease in tumor growth, with no adverse effect on body weight. Collectively, this study highlights the import...
Source: Sarcoma - October 3, 2020 Category: Cancer & Oncology Tags: Sarcoma Source Type: research

Characterization of GRK5 as a novel regulator of rhabdomyosarcoma tumor cell growth and self-renewal.
Authors: Pham T, Robinson K, Vleeshouwer-Neumann T, Annis JE, Chen EY Abstract Rhabdomyosarcoma (RMS) is the most common soft-tissue pediatric sarcoma. Clinical outcomes for RMS patients with relapsed or metastatic disease remain poor. Treatment options remain limited, presenting an urgent need for novel therapeutic targets. Using a high-throughput siRNA screen against the human kinome, we identified GRK5, a G-protein receptor kinase, as a novel regulator of RMS tumor cell growth and self-renewal. Through functional assays in vitro and in vivo, we show that GRK5 regulates cell cycle in a kinase-independent manner t...
Source: Oncotarget - May 5, 2020 Category: Cancer & Oncology Tags: Oncotarget Source Type: research

Targeting ALK in pediatric RMS does not induce antitumor activity in vivo
ConclusionsWhile ALK appears to be a relevant target in RMS in vitro, targeting this kinase in vivo yields no therapeutic efficacy, warranting extreme caution when considering the use of these agents in pediatric RMS patients.
Source: Cancer Chemotherapy and Pharmacology - May 31, 2018 Category: Cancer & Oncology Source Type: research

Hedgehog signaling negatively co-regulates BH3-only protein Noxa and TAp73 in TP53-mutated cells
In the present study, we show that pharmacological repression by the Hedgehog (Hh) pathway inhibitor (HPI) GANT61 induces expression of the proapoptotic protein Noxa in TP53-mutated embryonal pediatric tumor cells driven by Hh signaling (i.e. rhabdomyosarcoma (RMS) and medulloblastoma (MB)). Similarly, genetic silencing of Gli1 by siRNA causes increased Noxa mRNA and protein levels, while overexpression of Gli1 results in decreased Noxa expression. Furthermore, TAp73 mRNA and protein levels are increased upon Gli1 knockdown, while Gli1 overexpression reduces TAp73 mRNA and protein levels.
Source: Cancer Letters - April 24, 2018 Category: Cancer & Oncology Authors: Michael Torsten Meister, Cathinka Boedicker, Thomas Klingebiel, Simone Fulda Tags: Original Articles Source Type: research

MET/ERK2 pathway regulates the motility of human alveolar rhabdomyosarcoma cells.
In this study, we demonstrated the functions of MET signaling in ARMS in vitro by using three human ARMS cell lines and three human embryonal rhabdomyosarcoma (ERMS) cell lines. MET mRNA levels and MET protein expression in ARMS cell lines was higher than those in ERMS cell lines as detected by real-time quantitative PCR and western blotting, respectively. Based on cell growth and cell cycle analyses it was found that HGF stimulation did not enhance the proliferation of ERMS or ARMS cell lines. HGF-stimulated cell motility of ARMS cell lines was inhibited by U0126 (ERK1/2 inhibitor) but was only partially inhibited by PD9...
Source: Oncology Reports - November 16, 2016 Category: Cancer & Oncology Tags: Oncol Rep Source Type: research

Role of HO-1-ROS-HDAC4-miR-206 Axis in RMS
Rhabdomyosarcoma (RMS) is an aggressive soft tissue cancer characterized by disturbed myogenic differentiation. Here we report a role for the oxidative stress response factor HO-1 in progression of RMS. We found that HO-1 was elevated and its effector target miR-206 decreased in RMS cell lines and clinical primary tumors of the more aggressive alveolar phenotype (aRMS). In embryonal RMS (eRMS), HO-1 expression was induced by Pax3/7-FoxO1, an aRMS hallmark oncogene, followed by a drop in miR-206 levels. Inhibition of HO-1 by tin protoporphyrin (SnPP) or siRNA downregulated Pax3/7-FoxO1 target genes and induced a myogenic pr...
Source: Cancer Research - October 1, 2016 Category: Cancer & Oncology Authors: Ciesla, M., Marona, P., Kozakowska, M., Jez, M., Seczynska, M., Loboda, A., Bukowska-Strakova, K., Szade, A., Walawender, M., Kusior, M., Stepniewski, J., Szade, K., Krist, B., Yagensky, O., Urbanik, A., Kazanowska, B., Dulak, J., Jozkowicz, A. Tags: Molecular and Cellular Pathobiology Source Type: research

Abstract PR10: The chromatin remodeler CHD4 as a potential specific target for alveolar rhabdomyosarcoma therapy
Fusion-positive alveolar rhabdomyosarcoma (FP-RMS) is a paediatric tumour driven by an oncogenic fusion transcription factor, PAX3-FOXO1. Conventional chemotherapy is only effective for low risk patients which carry no metastasis, achieving a 5-year overall survival of 65%. The unique presence of this fusion protein in FP-RMS as well as the tumour cell survival dependency on PAX3-FOXO1 make this transcription factor a promising target for therapy. However, due to the difficulties associated with drug development targeting transcription factors, we performed a combined proteomic and genetic screen to identify new druggable ...
Source: Cancer Research - April 3, 2016 Category: Cancer & Oncology Authors: Marques, J., Boehm, M., Wachtel, M., Schaefer, B. Tags: Epigenetics Source Type: research

FOXM1 expression in rhabdomyosarcoma: a novel prognostic factor and therapeutic target
This study aimed to determine the role of FOXM1 in RMS. We investigated the expression levels of FOXM1 and vascular endothelial growth factor (VEGF) and angiogenesis in a large series of RMS clinical cases using immunohistochemistry (n = 92), and we performed clinicopathologic and prognostic analyses. In vitro studies were conducted to examine the effect of FOXM1 knock-down on VEGF expression, cell proliferation, migration, and invasion in embryonal RMS (ERMS) and alveolar RMS (ARMS) cell lines, using small interference RNA (siRNA). High FOXM1 expression was significantly increased in the cases of ARMS, which has an ad...
Source: Tumor Biology - November 9, 2015 Category: Cancer & Oncology Source Type: research

Crizotinib-induced antitumour activity in human alveolar rhabdomyosarcoma cells is not solely dependent on ALK and MET inhibition
Conclusions: These results provide a further insight into the molecular mechanisms affected by crizotinib in ARMS cells inferring that it could be a useful therapeutic tool in ARMS cancer treatment.
Source: Journal of Experimental and Clinical Cancer Research - October 6, 2015 Category: Cancer & Oncology Authors: Francesca MegiorniHeather McDowellSimona CameroOlga MannarinoSimona CeccarelliMilena PaianoPaul LostyBarry PizerRajeev ShuklaAntonio PizzutiAnna ClericoCarlo Dominici Source Type: research

Abstract 487: Whole genome screen to identify genes targeting MYCN-driven embryonal tumors
MYCN is a driver of neuroblastoma (NB) tumorigenesis and is over-expressed in a number of tumors of embryonal origin, including rhabdomyosarcoma, medulloblastoma and diffuse intrinsic pontine gliomas. We sought to identify regulators of MYCN transcription by performing a whole genome screen (WGS) for regulators of MYCN promoter activity using a NB cell model. A plasmid containing the MYCN promoter (1.3kb upstream of MYCN TSS) fused to luciferase and stably integrated into the genome of NGP NB cells was the readout system. NGP-MYCNpluc, was selected based on MYCN luciferase activity inhibition by ATRA and HDAC inhibitors to...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Thiele, C. J., Liu, Z., Veschi, V., Buehler, E., Martin, S. Tags: Tumor Biology Source Type: research

Abstract 3792: SKP2 supports cell proliferation and is regulated by Notch signaling in myoblasts and embryonal rhabdomyosarcoma
Conclusion:Altogether, these preliminary experiments suggest that SKP2 could be regulated by Notch signaling in ERMS and that its inhibition hampers tumor cell proliferative capability.Note: This abstract was not presented at the meeting.Citation Format: Rossella Rota, Laura Adesso, Beatrice Conti, Roberta Ciarapica, Lavinia Raimondi, Maria De Salvo, Sonia Rodriguez, Nadia Carlesso, Lucio Miele, Franco Locatelli. SKP2 supports cell proliferation and is regulated by Notch signaling in myoblasts and embryonal rhabdomyosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Rese...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Rota, R., Adesso, L., Conti, B., Ciarapica, R., De Raimondi, L., Salvo, M., Rodriguez, S., Carlesso, N., Miele, L., Locatelli, F. Tags: Molecular and Cellular Biology Source Type: research

Chorein addiction in VPS13A overexpressing rhabdomyosarcoma cells.
In conclusion, chorein is expressed in various cancer cells. In cells with high chorein expression levels chorein silencing promotes apoptotic cell death, an effect paralleled by down-regulation of PI-3K activity and BCL-2/Bax expression ratio. PMID: 25871399 [PubMed - as supplied by publisher]
Source: Oncotarget - April 17, 2015 Category: Cancer & Oncology Tags: Oncotarget Source Type: research

Targeting of PAX3-FOXO1 by PLK1 Inhibition
In this report, we addressed this challenge by developing a two-armed screen for druggable upstream regulatory kinases in the PAX3/7-FOXO1 pathway. Screening libraries of kinome siRNA and small molecules, we defined PLK1 as an upstream-acting regulator. Mechanistically, PLK1 interacted with and phosphorylated PAX3-FOXO1 at the novel site S503, leading to protein stabilization. Notably, PLK1 inhibition led to elevated ubiquitination and rapid proteasomal degradation of the PAX3-FOXO1 chimeric oncoprotein. On this basis, we embarked on a preclinical validation of PLK1 as a target in a xenograft mouse model of aRMS, where the...
Source: Cancer Research - January 4, 2015 Category: Cancer & Oncology Authors: Thalhammer, V., Lopez–Garcia, L. A., Herrero–Martin, D., Hecker, R., Laubscher, D., Gierisch, M. E., Wachtel, M., Bode, P., Nanni, P., Blank, B., Koscielniak, E., Schafer, B. W. Tags: Molecular and Cellular Pathobiology Source Type: research

Abstract PR02: Negative regulation of myogenesis by Mtor: A pathway toward differentiation therapy in rhabdomyosarcoma
Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, is composed of skeletal myoblast-like cells that have lost the capacity to terminally differentiate. This suggests that RMS cells may contain a factor that blocks normal muscle differentiation. Because cell cycle arrest is coupled to muscle differentiation, identifying putative negative regulators of differentiation could lead to novel therapeutic approaches aimed at fostering terminal differentiation. To gain insight into the events that normally trigger the initial phase of muscle differentiation, we carried out a high content cell-based screen usin...
Source: Cancer Research - October 9, 2014 Category: Cancer & Oncology Authors: Wilson, R. A., Liu, J., Xu, L., Zheng, Y., Skapek, S. X. Tags: Developmental Biology of Pediatric Malignancies Source Type: research

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