Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling

Estupiñán, Óscar; Rey, Verónica; Tornín, Juan; Murillo, Dzohara; Gallego, Borja; Huergo, Carmen; Blanco Lorenzo, Verónica; González Meana, M. Victoria; Rodríguez Pérez, Aida; Moris, Francisco; González Miranda, Jessica; Ayllón, Verónica; Ramos-Mejía, Verónica; Bigas Salvans, Anna; Rodríguez, René

Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling

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dc.contributor.author Estupiñán, Óscar
dc.contributor.author Rey, Verónica
dc.contributor.author Tornín, Juan
dc.contributor.author Murillo, Dzohara
dc.contributor.author Gallego, Borja
dc.contributor.author Huergo, Carmen
dc.contributor.author Blanco Lorenzo, Verónica
dc.contributor.author González Meana, M. Victoria
dc.contributor.author Rodríguez Pérez, Aida
dc.contributor.author Moris, Francisco
dc.contributor.author González Miranda, Jessica
dc.contributor.author Ayllón, Verónica
dc.contributor.author Ramos-Mejía, Verónica
dc.contributor.author Bigas Salvans, Anna
dc.contributor.author Rodríguez, René
dc.date.accessioned 2024-02-22T07:08:48Z
dc.date.available 2024-02-22T07:08:48Z
dc.date.issued 2023
dc.description.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.
dc.description.sponsorship This work was supported by the Agencia Estatal de Investigación (AEI) [MICINN/Fondo Europeo de Desarrollo Regional (FEDER) (grant PID2019–106666RB-I00 to R.R.) and ISC III/FEDER (Consorcio CIBERONC - CB16/12/00390)] and the Plan de Ciencia Tecnología e Innovación del Principado de Asturias/FEDER [grant IDI/2021/000027 and Severo Ochoa predoctoral fellowships BP-17–108 to O.E., BP‐ 20–046 to B.G. and BP-21–084 to DM].
dc.format.mimetype application/pdf
dc.identifier.citation Estupiñán Ó, Rey V, Tornín J, Murillo D, Gallego B, Huergo C, Blanco-Lorenzo V, Victoria González M, Rodríguez A, Moris F, González J, Ayllón V, Ramos-Mejía V, Bigas A, Rodríguez R. Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling. Biomed Pharmacother. 2023 Jun;162:114627. DOI: 10.1016/j.biopha.2023.114627
dc.identifier.doi http://dx.doi.org/10.1016/j.biopha.2023.114627
dc.identifier.issn 0753-3322
dc.identifier.uri http://hdl.handle.net/10230/59215
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Biomed Pharmacother. 2023 Jun;162:114627
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019–106666RB-I00
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Cancer stem cells
dc.subject.keyword EC-8042
dc.subject.keyword HES1
dc.subject.keyword Mithramycin
dc.subject.keyword NOTCH1
dc.subject.keyword Osteosarcoma
dc.subject.keyword Sarcoma
dc.title Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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