mTOR inhibition suppresses salinomycin-induced ferroptosis in breast cancer stem cells by ironing out mitochondrial dysfunctions.

Autor: Cosialls E; Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 5 and Ferostem group, F-75015, Paris, France.; Ferostem group, F-75015, Paris, France., Pacreau E; Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 5 and Ferostem group, F-75015, Paris, France., Duruel C; Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 5 and Ferostem group, F-75015, Paris, France.; Ferostem group, F-75015, Paris, France., Ceccacci S; Proteomic Core Facility, Université de Paris - Structure Fédérative de Recherche - Necker, INSERM US24/CNRS, UAR3633, Paris, France., Elhage R; Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 5 and Ferostem group, F-75015, Paris, France.; Ferostem group, F-75015, Paris, France., Desterke C; UFR Médecine-INSERM UMS33, Université Paris-Sud, F94800, Villejuif, France., Roger K; Proteomic Core Facility, Université de Paris - Structure Fédérative de Recherche - Necker, INSERM US24/CNRS, UAR3633, Paris, France., Guerrera C; Proteomic Core Facility, Université de Paris - Structure Fédérative de Recherche - Necker, INSERM US24/CNRS, UAR3633, Paris, France., Ducloux R; Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 5 and Ferostem group, F-75015, Paris, France.; Ferostem group, F-75015, Paris, France., Souquere S; CNRS, UMR9196, Villejuif, France - Gustave Roussy Cancer Campus, Villejuif, France., Pierron G; CNRS, UMR9196, Villejuif, France - Gustave Roussy Cancer Campus, Villejuif, France., Nemazanyy I; Metabolic Core Facility, Université de Paris - Structure Fédérative de Recherche - Necker, INSERM US24/CNRS, UAR3633, Paris, France., Kelly M; Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 5 and Ferostem group, F-75015, Paris, France., Dalmas E; Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 5 and Ferostem group, F-75015, Paris, France., Chang Y; Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 5 and Ferostem group, F-75015, Paris, France., Goffin V; Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 5 and Ferostem group, F-75015, Paris, France., Mehrpour M; Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 5 and Ferostem group, F-75015, Paris, France.; Ferostem group, F-75015, Paris, France., Hamaï A; Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 5 and Ferostem group, F-75015, Paris, France. ahmed.hamai@inserm.fr.; Ferostem group, F-75015, Paris, France. ahmed.hamai@inserm.fr.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2023 Nov 15; Vol. 14 (11), pp. 744. Date of Electronic Publication: 2023 Nov 15.
DOI: 10.1038/s41419-023-06262-5
Abstrakt: 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 CD24 low /CD44 high ), 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: