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

Cosialls, E.; Pacreau, E.; Ceccacci, S.; Elhage, R.; Duruel, C.; Desterke, C.; Roger, K.; Guerrera, C.; Ducloux, R.; Souquere, S.; Pierron, G.; Nemazanyy, I.; Kelly, M.; Dalmas, E.; Chang, Y.; Goffin, V.; Mehrpour, M.; Hamai, A.

doi:10.1101/2023.05.02.539040

bioRxiv · 10.1101/2023.05.02.539040

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

Cosialls, E.·Pacreau, E.·Ceccacci, S.·Elhage, R.·Duruel, C.·Desterke, C.·Roger, K.·Guerrera, C.·Ducloux, R.·Souquere, S.·Pierron, G.·Nemazanyy, I.·Kelly, M.·Dalmas, E.·Chang, Y.·Goffin, V.·Mehrpour, M.·Hamai, A.

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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. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/539040v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@8b8772org.highwire.dtl.DTLVardef@695e0forg.highwire.dtl.DTLVardef@19e3f83org.highwire.dtl.DTLVardef@5bc0a6_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Cosialls, E., Pacreau, E., Ceccacci, S., Elhage, R., Duruel, C., Desterke, C., Roger, K., Guerrera, C., Ducloux, R., Souquere, S., Pierron, G., Nemazanyy, I., Kelly, M., Dalmas, E., Chang, Y., Goffin, V., Mehrpour, M., Hamai, A.. 2023-05-02. mTOR Inhibition Suppresses Salinomycin-Induced Ferroptosis in Breast Cancer Stem Cells by Ironing Out Mitochondrial Dysfunctions. https://doi.org/10.1101/2023.05.02.539040

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