@article{7354139c924a4c958a7f5a81e9a7e165,
title = "AMPK-Mediated BECN1 Phosphorylation Promotes Ferroptosis by Directly Blocking System Xc – Activity",
abstract = "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. Song et al. find that BECN1 promotes ferroptosis by directly blocking system Xc– activity via binding to its core component SLC7A11. This pathway is different from the previously identified function of BECN1 as a positive regulator of autophagy via directly activating PtdIns3K activity via binding to its core component PIK3C3.",
keywords = "AMPK, BECN1, SLC7A11, autophagy, autosis, cancer therapy, ferroptosis, lipid peroxidation, necroptosis, phosphorylation",
author = "Xinxin Song and Shan Zhu and Pan Chen and Wen Hou and Qirong Wen and Jiao Liu and Yangchun Xie and Jinbao Liu and Klionsky, {Daniel J.} and Guido Kroemer and Lotze, {Michael T.} and Zeh, {Herbert J.} and Rui Kang and Daolin Tang",
note = "Funding Information: We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from the US NIH (R01GM115366, R01CA160417, R01CA211070, and R01GM053396), the Natural Science Foundation of Guangdong Province (2016A030308011), the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD), the National Natural Science Foundation of China (31671435, 81400132, and 81772508), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017), Lin He's Academician Workstation of New Medicine and Clinical Translation (2017), and International Scientific and Technology Cooperation Program of China (2015DFA31490). This project partly utilized University of Pittsburgh Cancer Institute shared resources supported by award P30CA047904. G.K. is supported by the Ligue contre le Cancer Comit{\'e} de Charente-Maritime ({\'e}quipe labelis{\'e}e), Agence National de la Recherche (ANR) – Projets blancs, ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases, Association pour la Recherche sur le Cancer (ARC), Canc{\'e}rop{\^o}le Ile-de-France, Chancelerie des universit{\'e}s de Paris (Legs Poix), Fondation pour la Recherche M{\'e}dicale, the European Commission, the European Research Council (ERC), Fondation Carrefour, Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, LeDucq Foundation, the LabEx Immuno-Oncology, the RHU Torino Lumi{\`e}re, the Searave Foundation, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), the SIRIC Cancer Research and Personalized Medicine (CARPEM), and the Paris Alliance of Cancer Research Institutes (PACRI). Funding Information: We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from the US NIH ( R01GM115366 , R01CA160417 , R01CA211070 , and R01GM053396 ), the Natural Science Foundation of Guangdong Province ( 2016A030308011 ), the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD ), the National Natural Science Foundation of China ( 31671435 , 81400132 , and 81772508 ), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017) , Lin He{\textquoteright}s Academician Workstation of New Medicine and Clinical Translation (2017) , and International Scientific and Technology Cooperation Program of China ( 2015DFA31490 ). This project partly utilized University of Pittsburgh Cancer Institute shared resources supported by award P30CA047904 . G.K. is supported by the Ligue contre le Cancer Comit{\'e} de Charente-Maritime ({\'e}quipe labelis{\'e}e) , Agence National de la Recherche (ANR) – Projets blancs , ANR under the frame of E-Rare-2 , the ERA-Net for Research on Rare Diseases , Association pour la Recherche sur le Cancer (ARC) , Canc{\'e}rop{\^o}le Ile-de-France , Chancelerie des universit{\'e}s de Paris (Legs Poix) , Fondation pour la Recherche M{\'e}dicale , the European Commission , the European Research Council (ERC) , Fondation Carrefour, Institut National du Cancer (INCa) , Inserm (HTE) , Institut Universitaire de France , LeDucq Foundation , the LabEx Immuno-Oncology , the RHU Torino Lumi{\`e}re, the Searave Foundation , the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE) , the SIRIC Cancer Research and Personalized Medicine (CARPEM) , and the Paris Alliance of Cancer Research Institutes (PACRI) . ",
year = "2018",
month = aug,
day = "6",
doi = "10.1016/j.cub.2018.05.094",
language = "English (US)",
volume = "28",
pages = "2388--2399.e5",
journal = "Current Biology",
issn = "0960-9822",
publisher = "Cell Press",
number = "15",
}