mTOR Inhibition Suppresses Salinomycin-Induced Ferroptosis in Breast Cancer Stem Cells by Ironing Out Mitochondrial Dysfunctions - Archive ouverte HAL Access content directly
Journal Articles (Data Paper) Cell Death and Disease Year : 2023

mTOR Inhibition Suppresses Salinomycin-Induced Ferroptosis in Breast Cancer Stem Cells by Ironing Out Mitochondrial Dysfunctions

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 mechanistic target of rapamycin (mTOR), suppresses Sal-induced ferroptosis. Mechanistically, mTOR inhibition modulates iron cellular flux and prevents the iron and ROS bursts induced by Sal. Besides, integration of multi-omics data identified mitochondria as a key target of Sal action. We demonstrated that mTOR inhibition prevents Sal-induced mitochondrial functional and structural alteration, and that Sal-induced metabolic plasticity is mainly dependent on the mTOR pathway. Overall, our findings provide experimental evidences on the detailed mechanisms of mTOR as a crucial effector of Sal-induced ferroptosis, and gives proof-of-concept that careful evaluation of such combination therapy (here mTOR and ferroptosis co-targeting) is required for effective treatment.
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Dates and versions

hal-04295475 , version 1 (20-11-2023)

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Emma Cosialls, Emeline Pacreau, Sara Ceccacci, Rima Elhage, Clémence Duruel, et al.. mTOR Inhibition Suppresses Salinomycin-Induced Ferroptosis in Breast Cancer Stem Cells by Ironing Out Mitochondrial Dysfunctions. Cell Death and Disease, 2023, 14, ⟨10.1038/s41419-023-06262-5⟩. ⟨hal-04295475⟩
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