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Cell Rep. 2018 Jan 16;22(3):569-575. doi: 10.1016/j.celrep.2017.12.077.

p53 Suppresses Metabolic Stress-Induced Ferroptosis in Cancer Cells.

Author information

1
Program in Cancer Biology, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA.
2
Department of Biology, Stanford University, 337 Campus Drive, Stanford, CA 94305, USA.
3
Department of Radiation Oncology, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA.
4
Program in Cancer Biology, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA; Department of Radiation Oncology, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA.
5
Program in Cancer Biology, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA; Department of Radiation Oncology, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA.
6
Program in Cancer Biology, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA; Department of Biology, Stanford University, 337 Campus Drive, Stanford, CA 94305, USA. Electronic address: sjdixon@stanford.edu.

Abstract

How cancer cells respond to nutrient deprivation remains poorly understood. In certain cancer cells, deprivation of cystine induces a non-apoptotic, iron-dependent form of cell death termed ferroptosis. Recent evidence suggests that ferroptosis sensitivity may be modulated by the stress-responsive transcription factor and canonical tumor suppressor protein p53. Using CRISPR/Cas9 genome editing, small-molecule probes, and high-resolution, time-lapse imaging, we find that stabilization of wild-type p53 delays the onset of ferroptosis in response to cystine deprivation. This delay requires the p53 transcriptional target CDKN1A (encoding p21) and is associated with both slower depletion of intracellular glutathione and a reduced accumulation of toxic lipid-reactive oxygen species (ROS). Thus, the p53-p21 axis may help cancer cells cope with metabolic stress induced by cystine deprivation by delaying the onset of non-apoptotic cell death.

KEYWORDS:

cancer; cell death; cystine; ferroptosis; glutathione; metabolism; p53; reactive oxygen species

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