Notch信号通路
赫斯1
骨肉瘤
癌症研究
信号转导
转录组
干细胞
生物
化学
细胞生物学
基因
生物化学
基因表达
作者
Óscar Estupiñán,Verónica Rey,Juan Tornín,Dzohara Murillo,Borja Gallego,Carmen Huergo,Verónica Blanco‐Lorenzo,Marı́a Victoria González,Aida Rodríguez,Francisco Morís,Jessica González,Verónica Ayllón,Verónica Ramos–Mejía,Anna Bigas,René Rodrı́guez
标识
DOI:10.1016/j.biopha.2023.114627
摘要
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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