Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine

Cell Reports

Scott W. Rowlinson¹  Christiaan Labuschagne²  David Mason³  Shira L. Cramer⁴  Kendra Triplett⁴  Everett Stone⁵  Ioannis Poursaitidis⁶  Thomas Crighton⁶  Xiaomeng Wang⁶  Olivier E. Pardo⁷  Rajat Roy⁷  Michael J. Seckl⁷  Richard F. Lamb⁸ 

[1] Aeglea BioTherapeutics, Austin, TX 78746, USA;Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK;Centre for Cell Imaging, Institute of Integrative Biology, University of Liverpool, Biosciences Building, Crown Street, Liverpool L69 7ZB, UK;Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712, USA;Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA;Department of Molecular and Clinical Cancer Medicine, University of Liverpool North West Cancer Research Centre, University of Liverpool, 200 London Road, Liverpool L69 7ZB, UK;Division of Cancer CRUK Laboratories, 1st Floor ICTEM Building, Hammersmith Hospital Campus of Imperial College London, Du Cane Road, London W120NN, UK;School of Health Sciences, Liverpool Hope University, Hope Park Campus, Liverpool L16 9JD, UK;

关键词: ferroptosis;    oncogene;    EGFR;    ROS;    MAPK;    GPX4;    NOX4;   

DOI  :  10.1016/j.celrep.2017.02.054

来源: DOAJ

【 摘 要 】

Cancer cells reprogram their metabolism, altering both uptake and utilization of extracellular nutrients. We individually depleted amino acid nutrients from isogenic cells expressing commonly activated oncogenes to identify correspondences between nutrient supply and viability. In HME (human mammary epithelial) cells, deprivation of cystine led to increased cell death in cells expressing an activated epidermal growth factor receptor (EGFR) mutant. Cell death occurred via synchronous ferroptosis, with generation of reactive oxygen species (ROS). Hydrogen peroxide promoted cell death, as both catalase and inhibition of NADPH oxidase 4 (NOX4) blocked ferroptosis. Blockade of EGFR or mitogen-activated protein kinase (MAPK) signaling similarly protected cells from ferroptosis, whereas treatment of xenografts derived from EGFR mutant non-small-cell lung cancer (NSCLC) with a cystine-depleting enzyme inhibited tumor growth in mice. Collectively, our results identify a potentially exploitable sensitization of some EGFR/MAPK-driven tumors to ferroptosis following cystine depletion.

【 授权许可】

Unknown