AMPK-mediated BECN1 phosphorylation Promotes Ferroptosis by Directly Blocking System Xc− Activity

By Xinxin Song, Shan Zhu, Pan Chen, Wen Hou, Qirong Wen, Jiao Liu, Yangchun Xie, Jinbao Liu, D. Klionsky, Guido Kroemer and 4 more. Current Biology, 2018

666 citations recorded by the source corpus.

Summary 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.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/e4d780c2c1eadb6da2d5b83b5f80268699018850

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. D. Tang
2. Guido Kroemer
3. R. Kang
4. Xin Chen
5. D. Klionsky
6. Jiao Liu
7. Chunhong Yan
8. T. Du

In Pulmonary and Respiratory Medicine

1. D. Tang
2. Guido Kroemer
3. R. Kang
4. Xin Chen
5. D. Klionsky
6. Jiao Liu
7. Brent R. Stockwell

Citations in the corpus

• Autophagy-Dependent Ferroptosis: Machinery and Regulation (2020, background): “In contrast, the administration of the BECN1 activator peptide Tatbeclin 1 enhances the anticancer activity of the SLC7A11/ system xc inhibitor through the induction of lipid peroxidation-dependent ferroptosis (Song et al., 2018).”
• Ferroptosis in infection, inflammation, and immunity (2021, background): “…11 (SLC7A11/xCT), is regulated by multiple mechanisms for controlling its activity, such as protein–protein interactions (e.g., by beclin 1 [BECN1]; Song et al., 2018), gene expression (e.g., by nuclear factor erythroid 2-like 2 [NFE2L2/NRF2]; Chen et al., 2017; tumor protein p53 [TP53]; Jiang…”
• ATF3 promotes erastin-induced ferroptosis by suppressing system Xc– (2019, background): “Previously, CD44v/MUC1-C and BECN1 was shown to interact with SLC7A11 and regulate the stability of system Xc [44, 45].”