Journal
CURRENT BIOLOGY
Volume 28, Issue 15, Pages 2388-+Publisher
CELL PRESS
DOI: 10.1016/j.cub.2018.05.094
Keywords
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Categories
Funding
- US NIH [R01GM115366, R01CA160417, R01CA211070, R01GM053396]
- Natural Science Foundation of Guangdong Province [2016A030308011]
- American Cancer Society [RSG-16-014-01-CDD]
- National Natural Science Foundation of China [31671435, 81400132, 81772508]
- Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017)
- Lin He's Academician Workstation of New Medicine and Clinical Translation (2017)
- International Scientific and Technology Cooperation Program of China [2015DFA31490]
- Ligue contre le Cancer Comite de Charente-Maritime (equipe labelisee)
- Agence National de la Recherche (ANR) - Projets blancs
- ERA-Net for Research on Rare Diseases
- Association pour la Recherche sur le Cancer (ARC)
- Canceropole Ile-de-France
- Chancelerie des universites de Paris (Legs Poix)
- Fondation pour la Recherche Medicale
- European Commission
- European Research Council (ERC)
- Fondation Carrefour
- Institut National du Cancer (INCa)
- Inserm (HTE)
- Institut Universitaire de France
- LeDucq Foundation
- LabEx Immuno-Oncology
- RHU Torino Lumiere
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Paris Alliance of Cancer Research Institutes (PACRI)
- Searave Foundation
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- [P30CA047904]
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Ferroptosis is a form of regulated cell death triggered by lipid peroxidation after inhibition of the cystine/glutamate antiporter system X-c(-). However, key regulators of system X-c(-) activity in ferroptosis remain undefined. Here, we show that BECN1 plays a hitherto unsuspected role in promoting ferroptosis through directly blocking system X-c(-) activity via binding to its core component, SLC7A11 (solute carrier family 7 member 11). Knockdown of BECN1 by shRNA inhibits ferroptosis induced by system X-c(-) inhibitors (e.g., erastin, sulfasalazine, and sorafenib), but not other ferroptosis inducers including RSL3, FIN56, and buthionine sulfoximine. Mechanistically, AMP-activated protein kinase (AMPK)-mediated phosphorylation of BECN1 at Ser90/93/96 is required for BECN1-SLC7A11 complex formation and lipid peroxidation. Inhibition of PRKAA/AMPKa by siRNA or compound C diminishes erastin-induced BECN1 phosphorylation at S93/96, BECN1-SLC7A11 complex formation, and subsequent ferroptosis. Accordingly, a BECN1 phosphorylation-defective mutant (S90,93,96A) reverses BECN1-induced lipid peroxidation and ferroptosis. Importantly, genetic and pharmacological activation of the BECN1 pathway by overexpression of the protein in tumor cells or by administration of the BECN1 activator peptide Tat-beclin 1, respectively, increases ferroptotic cancer cell death (but not apoptosis and necroptosis) in vitro and in vivo in subcutaneous and orthotopic tumor mouse models. Collectively, our work reveals that BECN1 plays a novel role in lipid peroxidation that could be exploited to improve anticancer therapy by the induction of ferroptosis.
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