p53 Suppresses Metabolic Stress-Induced Ferroptosis in Cancer Cells

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 t...

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Published in:Cell reports (Cambridge) 2018-01, Vol.22 (3), p.569-575
Main Authors: Tarangelo, Amy, Magtanong, Leslie, Bieging-Rolett, Kathryn T., Li, Yang, Ye, Jiangbin, Attardi, Laura D., Dixon, Scott J.
Format: Article
Language:English
Subjects:
Animals
Apoptosis - physiology
cancer
cell death
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
cystine
ferroptosis
glutathione
Glutathione - metabolism
Humans
metabolism
Mice
Neoplasms - genetics
Neoplasms - metabolism
Neoplasms - pathology
p53
reactive oxygen species
Reactive Oxygen Species - metabolism
Tumor Suppressor Protein p53 - metabolism
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Summary: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. [Display omitted] •p53 stabilization can delay the induction of ferroptosis in cancer cells•This effect requires the p53 transcriptional target gene CDKN1A (p21)•Cell-cycle arrest per se may not be sufficient to inhibit ferroptosis•Inhibition of ferroptosis correlates with conservation of glutathione Tarangelo et al. show that stabilization of wild-type p53, leading to expression of the downstream target CDKN1A (encoding p21CIP1/WAF1), delays the onset of ferroptosis in response to subsequent cystine deprivation in human and in mouse cancer cells.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2017.12.077