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GLS2 is protumorigenic in breast cancers

Oncogene volume 39, pages 690–702 (2020)Cite this article

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Abstract

Many types of cancers have a well-established dependence on glutamine metabolism to support survival and growth, a process linked to glutaminase 1 (GLS) isoforms. Conversely, GLS2 variants often have tumor-suppressing activity. Triple-negative (TN) breast cancer (testing negative for estrogen, progesterone, and Her2 receptors) has elevated GLS protein levels and reportedly depends on exogenous glutamine and GLS activity for survival. Despite having high GLS levels, we verified that several breast cancer cells (including TN cells) express endogenous GLS2, defying its role as a bona fide tumor suppressor. Moreover, ectopic GLS2 expression rescued cell proliferation, TCA anaplerosis, redox balance, and mitochondrial function after GLS inhibition by the small molecule currently in clinical trials CB-839 or GLS knockdown of GLS-dependent cell lines. In several cell lines, GLS2 knockdown decreased cell proliferation and glutamine-linked metabolic phenotypes. Strikingly, long-term treatment of TN cells with another GLS-exclusive inhibitor bis-2′-(5-phenylacetamide-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) selected for a drug-resistant population with increased endogenous GLS2 and restored proliferative capacity. GLS2 was linked to enhanced in vitro cell migration and invasion, mesenchymal markers (through the ERK-ZEB1-vimentin axis under certain conditions) and in vivo lung metastasis. Of concern, GLS2 amplification or overexpression is linked to an overall, disease-free and distant metastasis-free worse survival prognosis in breast cancer. Altogether, these data establish an unforeseen role of GLS2 in sustaining tumor proliferation and underlying metastasis in breast cancer and provide an initial framework for exploring GLS2 as a novel therapeutic target.

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Acknowledgements

This work was supported by the São Paulo State Research Foundation, FAPESP, under grants 2012/14298-9 (ALBA) and 2014/20673-2 (ALBA), 2014/15968-3 (SMGD), 2015/25832-4 (SMGD) and fellowships 2013/05668-0 (IMF) 2013/23510-4 (CFRA), 2012/11577-4 (MMD), 2014/18061-9 (LMR), 2014/17820-3 (DAM), 2016/06625-0 (ACPM), 2014/06512-6 (KRSO), 2011/10127-2 (CAGC), and 2012/09452-9 (MQE). We thank LNBio for financial support and access to all facilities (PBQT, LCCMI, LPP, LEC, LVV, and LIB). Data used in this publication were generated by the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium (CPTAC). The results published here are in whole or part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/. We thank Dr Alessandra Girasole for expert technical support. GAC is the Felix L. Haas Endowed Professor in Basic Science. Work in GAC’s laboratory is supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC), the NCI grants 1R01 CA182905-01 and 1R01CA222007-01A1, an NIGMS 1R01GM122775-01 grant, a U54 grant #CA096297/CA096300 – UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project, a Team DOD (CA160445P1) grant, a Chronic Lymphocytic Leukemia Moonshot Flagship project, a Sister Institution Network Fund (SINF) 2017 grant, and the Estate of C. G. Johnson, Jr.

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Author notes

  1. Andre Luis Berteli Ambrosio

    Present address: Sao Carlos Institute of Physics (IFSC), University of Sao Paulo (USP), Sao Carlos, Sao Paulo, 13563-120, Brazil

  2. These authors contributed equally: Marilia M. Dias, Douglas Adamoski, Larissa M. dos Reis, Carolline F.R. Ascenção

  3. These authors jointly supervised: Andre L.B. Ambrosio, Sandra M.G. Dias

Authors and Affiliations

  1. Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Sao Paulo, 13083-970, Brazil

    Marilia M. Dias, Douglas Adamoski, Larissa M. dos Reis, Carolline F. R. Ascenção, Krishina R. S. de Oliveira, Ana Carolina Paschoalini Mafra, Alliny Cristiny da Silva Bastos, Melissa Quintero, Carolina de G. Cassago, Igor M. Ferreira, Silvana A. Rocco, Marcio Chaim Bajgelman, Andre Luis Berteli Ambrosio & Sandra Martha Gomes Dias

  2. Graduate Program in Genetics and Molecular Biology, Institute of Biology University of Campinas (UNICAMP), Campinas, Sao Paulo, Brazil

    Marilia M. Dias, Douglas Adamoski, Larissa M. dos Reis, Carolline F. R. Ascenção, Krishina R. S. de Oliveira, Ana Carolina Paschoalini Mafra & Alliny Cristiny da Silva Bastos

  3. ThoMSon Mass Spectrometry Laboratory, Institute of Chemistry, University of Campinas, Campinas, Sao Paulo, 13083-970, Brazil

    Carlos H. V. Fidelis

  4. The Wistar Institute, 3601 Spruce Street, Philadelphia, PA, 19104, USA

    Zachary Stine

  5. Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy “Iuliu-Hatieganu”, 400337, Cluj-Napoca, Romania

    Ioana Berindan-Neagoe

  6. MedFuture Research Center for Advanced Medicine, University of Medicine and Pharmacy “Iuliu-Hatieganu”, 400349, Cluj-Napoca, Romania

    Ioana Berindan-Neagoe

  7. Department of Functional Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuţă”, 400015, Cluj-Napoca, Romania

    Ioana Berindan-Neagoe

  8. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1950, Houston, TX, 77030, USA

    George A. Calin

  9. Center for RNA Inference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1950, Houston, TX, 77030, USA

    George A. Calin

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  1. Marilia M. Dias
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Dias, M.M., Adamoski, D., dos Reis, L.M. et al. GLS2 is protumorigenic in breast cancers. Oncogene 39, 690–702 (2020). https://doi.org/10.1038/s41388-019-1007-z

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