| Autor: |
Emma Cosialls, Emeline Pacreau, Clémence Duruel, Sara Ceccacci, Rima Elhage, Christophe Desterke, Kevin Roger, Chiara Guerrera, Romane Ducloux, Sylvie Souquere, Gérard Pierron, Ivan Nemazanyy, Mairead Kelly, Elise Dalmas, Yunhua Chang, Vincent Goffin, Maryam Mehrpour, Ahmed Hamaï |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Cell Death and Disease, Vol 14, Iss 11, Pp 1-14 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2041-4889 |
| DOI: |
10.1038/s41419-023-06262-5 |
| Popis: |
Abstract Ferroptosis constitutes a promising therapeutic strategy against cancer by efficiently targeting the highly tumorigenic and treatment-resistant cancer stem cells (CSCs). We previously showed that the lysosomal iron-targeting drug Salinomycin (Sal) was able to eliminate CSCs by triggering ferroptosis. Here, in a well-established breast CSCs model (human mammary epithelial HMLER CD24low/CD44high), we identified that pharmacological inhibition of the mechanistic target of rapamycin (mTOR), suppresses Sal-induced ferroptosis. Mechanistically, mTOR inhibition modulates iron cellular flux and thereby limits iron-mediated oxidative stress. Furthermore, integration of multi-omics data identified mitochondria as a key target of Sal action, leading to profound functional and structural alteration prevented by mTOR inhibition. On top of that, we found that Sal-induced metabolic plasticity is mainly dependent on the mTOR pathway. Overall, our findings provide experimental evidence for the mechanisms of mTOR as a crucial effector of Sal-induced ferroptosis pointing not only that metabolic reprogramming regulates ferroptosis, but also providing proof-of-concept that careful evaluation of such combination therapy (here mTOR and ferroptosis co-targeting) is required in the development of an effective treatment. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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