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The c-Myc/AKT1/TBX3 Axis Is Important to Target in the Treatment of Embryonal Rhabdomyosarcoma

Rhabdomyosarcoma is a highly aggressive malignant cancer that arises from skeletal muscle progenitor cells and is the third most common solid tumour in children. Despite significant advances, rhabdomyosarcoma still presents a therapeutic challenge, and while targeted therapy has shown promise, there...

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Autores principales: Sims, Danica, Maranyane, Hapiloe Mabaruti, Damerell, Victoria, Govender, Dhirendra, Isaacs, Ashwin W., Peres, Jade, Prince, Sharon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072582/
https://www.ncbi.nlm.nih.gov/pubmed/32098189
http://dx.doi.org/10.3390/cancers12020501
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author Sims, Danica
Maranyane, Hapiloe Mabaruti
Damerell, Victoria
Govender, Dhirendra
Isaacs, Ashwin W.
Peres, Jade
Prince, Sharon
author_facet Sims, Danica
Maranyane, Hapiloe Mabaruti
Damerell, Victoria
Govender, Dhirendra
Isaacs, Ashwin W.
Peres, Jade
Prince, Sharon
author_sort Sims, Danica
collection PubMed
description Rhabdomyosarcoma is a highly aggressive malignant cancer that arises from skeletal muscle progenitor cells and is the third most common solid tumour in children. Despite significant advances, rhabdomyosarcoma still presents a therapeutic challenge, and while targeted therapy has shown promise, there are limited options because the molecular drivers of rhabdomyosarcoma are poorly understood. We previously reported that the T-box transcription factor 3 (TBX3), which has been identified as a druggable target in many cancers, is overexpressed in rhabdomyosarcoma patient samples and cell lines. To identify new molecular therapeutic targets to treat rhabdomyosarcoma, this study investigates the potential oncogenic role(s) for TBX3 and the factors responsible for upregulating it in this cancer. To this end, rhabdomyosarcoma cell culture models in which TBX3 was either stably knocked down or overexpressed were established and the impact on key hallmarks of cancer were examined using growth curves, soft agar and scratch motility assays, as well as tumour-forming ability in nude mice. Our data show that TBX3 promotes substrate-dependent and -independent proliferation, migration and tumour formation. We further reveal that TBX3 is upregulated by c-Myc transcriptionally and AKT1 post-translationally. This study identifies c-Myc/AKT1/TBX3 as an important axis that could be targeted for the treatment of rhabdomyosarcoma.
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spelling pubmed-70725822020-03-19 The c-Myc/AKT1/TBX3 Axis Is Important to Target in the Treatment of Embryonal Rhabdomyosarcoma Sims, Danica Maranyane, Hapiloe Mabaruti Damerell, Victoria Govender, Dhirendra Isaacs, Ashwin W. Peres, Jade Prince, Sharon Cancers (Basel) Article Rhabdomyosarcoma is a highly aggressive malignant cancer that arises from skeletal muscle progenitor cells and is the third most common solid tumour in children. Despite significant advances, rhabdomyosarcoma still presents a therapeutic challenge, and while targeted therapy has shown promise, there are limited options because the molecular drivers of rhabdomyosarcoma are poorly understood. We previously reported that the T-box transcription factor 3 (TBX3), which has been identified as a druggable target in many cancers, is overexpressed in rhabdomyosarcoma patient samples and cell lines. To identify new molecular therapeutic targets to treat rhabdomyosarcoma, this study investigates the potential oncogenic role(s) for TBX3 and the factors responsible for upregulating it in this cancer. To this end, rhabdomyosarcoma cell culture models in which TBX3 was either stably knocked down or overexpressed were established and the impact on key hallmarks of cancer were examined using growth curves, soft agar and scratch motility assays, as well as tumour-forming ability in nude mice. Our data show that TBX3 promotes substrate-dependent and -independent proliferation, migration and tumour formation. We further reveal that TBX3 is upregulated by c-Myc transcriptionally and AKT1 post-translationally. This study identifies c-Myc/AKT1/TBX3 as an important axis that could be targeted for the treatment of rhabdomyosarcoma. MDPI 2020-02-21 /pmc/articles/PMC7072582/ /pubmed/32098189 http://dx.doi.org/10.3390/cancers12020501 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sims, Danica
Maranyane, Hapiloe Mabaruti
Damerell, Victoria
Govender, Dhirendra
Isaacs, Ashwin W.
Peres, Jade
Prince, Sharon
The c-Myc/AKT1/TBX3 Axis Is Important to Target in the Treatment of Embryonal Rhabdomyosarcoma
title The c-Myc/AKT1/TBX3 Axis Is Important to Target in the Treatment of Embryonal Rhabdomyosarcoma
title_full The c-Myc/AKT1/TBX3 Axis Is Important to Target in the Treatment of Embryonal Rhabdomyosarcoma
title_fullStr The c-Myc/AKT1/TBX3 Axis Is Important to Target in the Treatment of Embryonal Rhabdomyosarcoma
title_full_unstemmed The c-Myc/AKT1/TBX3 Axis Is Important to Target in the Treatment of Embryonal Rhabdomyosarcoma
title_short The c-Myc/AKT1/TBX3 Axis Is Important to Target in the Treatment of Embryonal Rhabdomyosarcoma
title_sort c-myc/akt1/tbx3 axis is important to target in the treatment of embryonal rhabdomyosarcoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072582/
https://www.ncbi.nlm.nih.gov/pubmed/32098189
http://dx.doi.org/10.3390/cancers12020501
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