Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling
| Autor: | Óscar Estupiñán, Verónica Rey, Juan Tornín, Dzohara Murillo, Borja Gallego, Carmen Huergo, Verónica Blanco-Lorenzo, M. Victoria González, Aida Rodríguez, Francisco Moris, Jessica González, Verónica Ayllón, Verónica Ramos-Mejía, Anna Bigas, René Rodríguez |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Scopus |
| Popis: | 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 Agencia Estatal de Investigacion (AEI) [MICINN/Fondo Europeo de Desarrollo Regional (FEDER) PID2019106666RB-I00 Spanish Government CB16/12/00390 Plan de Ciencia Tecnologia e Innovacion del Principado de Asturias/FEDER IDI/2021/000027 BP-17108 BP-20046 BP-21084 |
| Databáze: | OpenAIRE |
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