PMID- 37968262
OWN - NLM
STAT- MEDLINE
DCOM- 20231127
LR  - 20240125
IS  - 2041-4889 (Electronic)
VI  - 14
IP  - 11
DP  - 2023 Nov 15
TI  - mTOR inhibition suppresses salinomycin-induced ferroptosis in breast cancer stem 
      cells by ironing out mitochondrial dysfunctions.
PG  - 744
LID - 10.1038/s41419-023-06262-5 [doi]
LID - 744
AB  - 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.
CI  - (c) 2023. The Author(s).
FAU - Cosialls, Emma
AU  - Cosialls E
AD  - Universite Paris Cite, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants 
      Malades, Team 5 and Ferostem group, F-75015, Paris, France.
AD  - Ferostem group, F-75015, Paris, France.
FAU - Pacreau, Emeline
AU  - Pacreau E
AD  - Universite Paris Cite, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants 
      Malades, Team 5 and Ferostem group, F-75015, Paris, France.
FAU - Duruel, Clemence
AU  - Duruel C
AD  - Universite Paris Cite, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants 
      Malades, Team 5 and Ferostem group, F-75015, Paris, France.
AD  - Ferostem group, F-75015, Paris, France.
FAU - Ceccacci, Sara
AU  - Ceccacci S
AUID- ORCID: 0000-0002-7918-0598
AD  - Proteomic Core Facility, Universite de Paris - Structure Federative de Recherche 
      - Necker, INSERM US24/CNRS, UAR3633, Paris, France.
FAU - Elhage, Rima
AU  - Elhage R
AD  - Universite Paris Cite, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants 
      Malades, Team 5 and Ferostem group, F-75015, Paris, France.
AD  - Ferostem group, F-75015, Paris, France.
FAU - Desterke, Christophe
AU  - Desterke C
AD  - UFR Medecine-INSERM UMS33, Universite Paris-Sud, F94800, Villejuif, France.
FAU - Roger, Kevin
AU  - Roger K
AUID- ORCID: 0000-0003-1353-3415
AD  - Proteomic Core Facility, Universite de Paris - Structure Federative de Recherche 
      - Necker, INSERM US24/CNRS, UAR3633, Paris, France.
FAU - Guerrera, Chiara
AU  - Guerrera C
AD  - Proteomic Core Facility, Universite de Paris - Structure Federative de Recherche 
      - Necker, INSERM US24/CNRS, UAR3633, Paris, France.
FAU - Ducloux, Romane
AU  - Ducloux R
AD  - Universite Paris Cite, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants 
      Malades, Team 5 and Ferostem group, F-75015, Paris, France.
AD  - Ferostem group, F-75015, Paris, France.
FAU - Souquere, Sylvie
AU  - Souquere S
AD  - CNRS, UMR9196, Villejuif, France - Gustave Roussy Cancer Campus, Villejuif, 
      France.
FAU - Pierron, Gerard
AU  - Pierron G
AD  - CNRS, UMR9196, Villejuif, France - Gustave Roussy Cancer Campus, Villejuif, 
      France.
FAU - Nemazanyy, Ivan
AU  - Nemazanyy I
AUID- ORCID: 0000-0001-8080-839X
AD  - Metabolic Core Facility, Universite de Paris - Structure Federative de Recherche 
      - Necker, INSERM US24/CNRS, UAR3633, Paris, France.
FAU - Kelly, Mairead
AU  - Kelly M
AD  - Universite Paris Cite, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants 
      Malades, Team 5 and Ferostem group, F-75015, Paris, France.
FAU - Dalmas, Elise
AU  - Dalmas E
AD  - Universite Paris Cite, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants 
      Malades, Team 5 and Ferostem group, F-75015, Paris, France.
FAU - Chang, Yunhua
AU  - Chang Y
AD  - Universite Paris Cite, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants 
      Malades, Team 5 and Ferostem group, F-75015, Paris, France.
FAU - Goffin, Vincent
AU  - Goffin V
AUID- ORCID: 0000-0002-8021-3086
AD  - Universite Paris Cite, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants 
      Malades, Team 5 and Ferostem group, F-75015, Paris, France.
FAU - Mehrpour, Maryam
AU  - Mehrpour M
AD  - Universite Paris Cite, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants 
      Malades, Team 5 and Ferostem group, F-75015, Paris, France.
AD  - Ferostem group, F-75015, Paris, France.
FAU - Hamai, Ahmed
AU  - Hamai A
AUID- ORCID: 0000-0002-7921-4014
AD  - Universite Paris Cite, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants 
      Malades, Team 5 and Ferostem group, F-75015, Paris, France. 
      ahmed.hamai@inserm.fr.
AD  - Ferostem group, F-75015, Paris, France. ahmed.hamai@inserm.fr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231115
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 62UXS86T64 (salinomycin)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - E1UOL152H7 (Iron)
SB  - IM
MH  - Humans
MH  - Female
MH  - *Ferroptosis
MH  - *Breast Neoplasms/drug therapy/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Iron/metabolism
MH  - Neoplastic Stem Cells/metabolism
PMC - PMC10651934
COIS- The authors declare no competing interests.
EDAT- 2023/11/16 00:42
MHDA- 2023/11/27 12:42
PMCR- 2023/11/15
CRDT- 2023/11/15 23:15
PHST- 2023/05/04 00:00 [received]
PHST- 2023/10/31 00:00 [accepted]
PHST- 2023/10/24 00:00 [revised]
PHST- 2023/11/27 12:42 [medline]
PHST- 2023/11/16 00:42 [pubmed]
PHST- 2023/11/15 23:15 [entrez]
PHST- 2023/11/15 00:00 [pmc-release]
AID - 10.1038/s41419-023-06262-5 [pii]
AID - 6262 [pii]
AID - 10.1038/s41419-023-06262-5 [doi]
PST - epublish
SO  - Cell Death Dis. 2023 Nov 15;14(11):744. doi: 10.1038/s41419-023-06262-5.