AMPK-Mediated BECN1 Phosphorylation Promotes Ferroptosis by Directly Blocking System Xc– Activity

• Published in: Current biology Vol. 28; no. 15; pp. 2388 - 2399.e5
• Main Authors: Song, Xinxin, Zhu, Shan, Chen, Pan, Hou, Wen, Wen, Qirong, Liu, Jiao, Xie, Yangchun, Liu, Jinbao, Klionsky, Daniel J., Kroemer, Guido, Lotze, Michael T., Zeh, Herbert J., Kang, Rui, Tang, Daolin
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 06.08.2018; Elsevier
• Subjects: AMPK; autophagy; autosis; BECN1; cancer therapy; ferroptosis; Life Sciences; lipid peroxidation; necroptosis; phosphorylation; SLC7A11; BECN1; cancer therapy; autophagy; ferroptosis; autosis; AMPK; SLC7A11; lipid peroxidation; phosphorylation; necroptosis
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2018.05.094

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. [Display omitted] •BECN1 is required for system Xc–-inhibitor-induced ferroptosis•BECN1 inhibits system Xc– activity through directly binding to SLC7A11•AMPK is required for BECN1 phosphorylation in ferroptosis•BECN1 contributes to the anticancer activity of ferroptosis in vivo 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.