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

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.

• Authors: Ioannis Poursaitidis, Xiaomeng Wang, Thomas Crighton, Christiaan Labuschagne, David Mason, Shira L Cramer, Kendra Triplett, Rajat Roy, Olivier E Pardo, Michael J Seckl, Scott W Rowlinson, Everett Stone, Richard F Lamb
• Journal: Cell reports (Cell Rep) Vol. 18 Issue 11 Pg. 2547-2556 (03 14 2017) ISSN: 2211-1247 [Electronic] United States
• PMID: 28297659 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Amino Acids
• Cystine
• Hydrogen Peroxide
• Iron
• Phospholipid Hydroperoxide Glutathione Peroxidase
• Glutathione Peroxidase
• ErbB Receptors
• Glutathione
• Cysteine

Topics

• Amino Acids (metabolism)
• Animals
• Breast (cytology)
• Carcinoma, Non-Small-Cell Lung (pathology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cysteine (metabolism)
• Cystine (pharmacology)
• Down-Regulation (drug effects)
• Epithelial Cells (drug effects, metabolism)
• ErbB Receptors (genetics)
• Female
• Glutathione (pharmacology)
• Glutathione Peroxidase (metabolism)
• Hydrogen Peroxide (metabolism)
• Iron (metabolism)
• Lung Neoplasms (pathology)
• MAP Kinase Signaling System (drug effects)
• Mice, SCID
• Mutation (genetics)
• Oncogenes
• Phospholipid Hydroperoxide Glutathione Peroxidase