The Role of Beclin 1-Dependent Autophagy in Cancer

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Abstract

Autophagy ( self-eating) is an intracellular degradation process used by cells to keep a “clean house”; as it degrades abnormal or damaged proteins and organelles, it helps to fight infections and also provides energy in times of fasting or exercising. Autophagy also plays a role in cancer, although its precise function in each cancer type is still obscure, and whether autophagy plays a protecting (through the clearing of damaged organelles and protein aggregates and preventing DNA damage) or a promoting (by fueling the already stablished tumor) role in cancer remains to be fully characterized. Beclin 1, the mammalian ortholog of yeast Atg6/Vps30, is an essential autophagy protein and has been shown to play a role in tumor suppression. Here, an update of the tumorigenesis regulation by Beclin 1-dependent autophagy is provided.

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Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.

Zhenyu Yue, Shengkan Jin, Chingwen Yang … (2003)

The biochemical properties of beclin 1 suggest a role in two fundamentally important cell biological pathways: autophagy and apoptosis. We show here that beclin 1-/- mutant mice die early in embryogenesis and beclin 1+/- mutant mice suffer from a high incidence of spontaneous tumors. These tumors continue to express wild-type beclin 1 mRNA and protein, establishing that beclin 1 is a haploinsufficient tumor suppressor gene. Beclin 1-/- embryonic stem cells have a severely altered autophagic response, whereas their apoptotic response to serum withdrawal or UV light is normal. These results demonstrate that beclin 1 is a critical component of mammalian autophagy and establish a role for autophagy in tumor suppression. They both provide a biological explanation for recent evidence implicating beclin 1 in human cancer and suggest that mutations in other genes operating in this pathway may contribute to tumor formation through deregulation of autophagy.

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Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex.

Yun Zhong, Qing Wang, Xianting Li … (2009)

Beclin 1, a mammalian autophagy protein that has been implicated in development, tumour suppression, neurodegeneration and cell death, exists in a complex with Vps34, the class III phosphatidylinositol-3-kinase (PI(3)K) that mediates multiple vesicle-trafficking processes including endocytosis and autophagy. However, the precise role of the Beclin 1-Vps34 complex in autophagy regulation remains to be elucidated. Combining mouse genetics and biochemistry, we have identified a large in vivo Beclin 1 complex containing the known proteins Vps34, p150/Vps15 and UVRAG, as well as two newly identified proteins, Atg14L (yeast Atg14-like) and Rubicon (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein). Characterization of the new proteins revealed that Atg14L enhances Vps34 lipid kinase activity and upregulates autophagy, whereas Rubicon reduces Vps34 activity and downregulates autophagy. We show that Beclin 1 and Atg14L synergistically promote the formation of double-membraned organelles that are associated with Atg5 and Atg12, whereas forced expression of Rubicon results in aberrant late endosomal/lysosomal structures and impaired autophagosome maturation. We hypothesize that by forming distinct protein complexes, Beclin 1 and its binding proteins orchestrate the precise function of the class III PI(3)K in regulating autophagy at multiple steps.

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

Michael T. Lotze, Guido Kroemer, Daniel Klionsky … (2018)

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 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 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/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.

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Journal

Journal ID (nlm-ta): Biology (Basel)

Journal ID (iso-abbrev): Biology (Basel)

Journal ID (publisher-id): biology

Title: Biology

Publisher: MDPI

ISSN (Electronic): 2079-7737

Publication date (Electronic): 22 December 2019

Publication date Collection: January 2020

Volume: 9

Issue: 1

Electronic Location Identifier: 4

Affiliations

[1 ]Institute for Cell Biology (Tumorforschung), University Hospital Essen, 45122 Essen, Germany; Silvia.Vega.Rubindecelis@ 123456gmail.com ; Tel.: +49-0201-723-3941

[2 ]German Cancer Consortium (DKTK) at Essen-Düsseldorf, 445122 Essen, Germany

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Publisher ID: biology-09-00004

DOI: 10.3390/biology9010004

PMC ID: 7168252

PubMed ID: 31877888

SO-VID: dfdce73d-6c93-4d89-ad29-8e7f4b355f90

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

The Role of Beclin 1-Dependent Autophagy in Cancer

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Cancer Metabolism

Most cited references 65

Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.

Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex.

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

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