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

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...

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Detalles Bibliográficos
Autores: Estupiñán, Óscar, Rey, Verónica, Tornín, Juan, Murillo, Dzohara, Gallego, Borja, Huergo, Carmen, Blanco-Lorenzo, Verónica, González Meana, M. Victoria|||0000-0001-9565-4899, Rodríguez, Aida, Moris, Francisco, González Miranda, Jessica|||0000-0001-7732-1564, Ayllon, Veronica, Ramos-Mejía, Verónica|||0000-0002-8013-4273, Bigas Salvans, Anna|||0000-0003-4801-6899, Rodríguez, René|||0000-0002-0768-7306
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:289206
Acceso en línea:https://ddd.uab.cat/record/289206
https://dx.doi.org/urn:doi:10.1016/j.biopha.2023.114627
Access Level:acceso abierto
Palabra clave:NOTCH1
HES1
EC-8042
Mithramycin
Sarcoma
Osteosarcoma
Cancer stem cells
Descripción
Sumario: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.

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