Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling
Estupiñán, Óscar (Instituto Universitario de Oncología del Principado de Asturias)
Rey, Verónica (Instituto Universitario de Oncología del Principado de Asturias)
Tornín, Juan (Instituto Universitario de Oncología del Principado de Asturias)
Murillo, Dzohara (Instituto Universitario de Oncología del Principado de Asturias)
Gallego, Borja (Instituto Universitario de Oncología del Principado de Asturias)
Huergo, Carmen (Instituto Universitario de Oncología del Principado de Asturias)
Blanco-Lorenzo, Verónica (Hospital Universitario Central de Asturias)
Victoria González, M. (Universidad de Oviedo)
Rodríguez, Aida (Instituto Universitario de Oncología del Principado de Asturias)
Moris, Francisco (EntreChem SL, Oviedo)
González Miranda, Jessica (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ayllon, Veronica (Universidad de Granada)
Ramos-Mejía, Verónica (Universidad de Granada)
Bigas Salvans, Anna (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Rodríguez, René (Instituto Universitario de Oncología del Principado de Asturias)

Date:	2023
Abstract:	Osteosarcomas are frequently associated to a poor prognosis and a modest response to current treatments. EC-8042 is a well-tolerated mithramycin analog that has demonstrated an efficient ability to eliminate tumor cells, including cancer stem cell subpopulations (CSC), in sarcomas. In transcriptomic and protein expression analyses, we identified NOTCH1 signaling as one of the main pro-stemness pathways repressed by EC-8042 in osteosarcomas. Overexpression of NOTCH-1 resulted in a reduced anti-tumor effect of EC-8042 in CSC-enriched 3D tumorspheres cultures. On the other hand, the depletion of the NOTCH-1 downstream target HES-1 was able to enhance the action of EC-8042 on CSCs. Moreover, HES1 depleted cells failed to recover after treatment withdrawal and showed reduced tumor growth potential in vivo. In contrast, mice xenografted with NOTCH1-overexpressing cells responded worse than parental cells to EC-8042. Finally, we found that active NOTCH1 levels in sarcoma patients was associated to advanced disease and lower survival. Overall, these data highlight the relevant role that NOTCH1 signaling plays in mediating stemness in osteosarcoma. Moreover, we demonstrate that EC-8042 is powerful inhibitor of NOTCH signaling and that the anti-CSC activity of this mithramycin analog highly rely on its ability to repress this pathway.
Grants:	Agencia Estatal de Investigación PID2019-106666RB-I00 Ministerio de Economía y Competitividad CB16/12/00390
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	NOTCH1 ; HES1 ; EC-8042 ; Mithramycin ; Sarcoma ; Osteosarcoma ; Cancer stem cells
Published in:	Biomedicine & pharmacotherapy, Vol. 162 (june 2023) , ISSN 1950-6007

DOI: 10.1016/j.biopha.2023.114627

12 p, 9.6 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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Articles > Published articles