AMPK-Mediated BECN1 Phosphorylation Promotes Ferroptosis by Directly Blocking System X(c)(-) Activity.

1. Curr Biol. 2018 Aug 6;28(15):2388-2399.e5. doi: 10.1016/j.cub.2018.05.094. Epub 2018 Jul 26.

AMPK-Mediated BECN1 Phosphorylation Promotes Ferroptosis by Directly Blocking System X(c)(-) Activity.

Song X(1), Zhu S(2), Chen P(3), Hou W(3), Wen Q(2), Liu J(2), Xie Y(4), Liu J(2), Klionsky DJ(5), Kroemer G(6), Lotze MT(3), Zeh HJ(3), Kang R(7), Tang D(8).

Author information: (1)The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA. (2)The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China. (3)Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA. (4)Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410008, China. (5)Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. (6)Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France; Institut National de la Santé et de la Recherche Médicale, U1138 Paris, France; Université Pierre et Marie Curie, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France; Department of Women’s and Children’s Health, Karolinska University Hospital, 17176 Stockholm, Sweden. (7)Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: kangr@upmc.edu. (8)The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: tangd2@upmc.edu.

Comment in Autophagy. 2018;14(12):2173-2175. doi: 10.1080/15548627.2018.1513758.

Ferroptosis is a form of regulated cell death triggered by lipid peroxidation after inhibition of the cystine/glutamate antiporter system Xc-. However, key regulators of system Xc- activity in ferroptosis remain undefined. Here, we show that BECN1 plays a hitherto unsuspected role in promoting ferroptosis through directly blocking system Xc- activity via binding to its core component, SLC7A11 (solute carrier family 7 member 11). Knockdown of BECN1 by shRNA inhibits ferroptosis induced by system Xc- 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/AMPKα 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.

Copyright © 2018 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.cub.2018.05.094 PMCID: PMC6081251 PMID: 30057310 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of Interests The authors declare no conflicts of interest or financial interests.