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

Poursaitidis, Ioannis and Wang, Xiaomeng and Crighton, Thomas and Labuschagne, Christiaan and Mason, David and Cramer, Shira L. and Triplett, Kendra and Roy, Rajat and Pardo, Olivier E. and Seckl, Michael J. and Rowlinson, Scott W. and Stone, Everett and Lamb, Richard F. (2017) Oncogene-Selective Sensitivity to Synchronous Cell Death following Modulation of the Amino Acid Nutrient Cystine. Cell Reports, 18 (11). pp. 2547-2556. ISSN 22111247

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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
Additional Information and Comments: “NOTICE: this is the author’s version of a work that was accepted for publication in Cell Reports. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Cell Reports, Volume 18, Issue 11, 14 March 2017 doi:10.1016/j.celrep.2017.02.054 Available under Creative Commons Attribution Non-Commercial No-Derivatives License
Keywords: Ferroptosis oncogene nutrient cancer
Faculty / Department: Faculty of Science > School of Health Sciences
Depositing User: Richard Lamb
Date Deposited: 27 Apr 2017 11:55
Last Modified: 27 Apr 2017 11:55
URI: https://hira.hope.ac.uk/id/eprint/1940

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