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



Poursaitidis, Ioannis, Wang, Xiaomeng, Crighton, Thomas, Labuschagne, Christiaan, Mason, David ORCID: 0000-0002-8773-5274, Cramer, Shira L, Triplett, Kendra, Roy, Rajat, Pardo, Olivier E, Seckl, Michael J
et al (show 3 more authors) (2017) Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine. CELL REPORTS, 18 (11). pp. 2547-2556.

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: Breast, Cell Line, Tumor, Epithelial Cells, Animals, Mice, SCID, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Hydrogen Peroxide, Cystine, Iron, Cysteine, Glutathione Peroxidase, Amino Acids, Glutathione, Cell Death, Cell Survival, MAP Kinase Signaling System, Down-Regulation, Mutation, Oncogenes, Female, ErbB Receptors, Phospholipid Hydroperoxide Glutathione Peroxidase
Depositing User: Symplectic Admin
Date Deposited: 27 Jul 2018 14:18
Last Modified: 16 Mar 2024 14:26
DOI: 10.1016/j.celrep.2017.02.054
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3024248