Ferroptosis as a p53-mediated activity during tumour suppression

Le Jiang, Ning Kon, Tongyuan Li, Shang-Jui Wang, Tao Su, Hanina Hibshoosh, Richard Baer and Wei Gu ()
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Le Jiang: Institute for Cancer Genetics, College of Physicians & Surgeons, Columbia University 1130 St Nicholas Ave
Ning Kon: Institute for Cancer Genetics, College of Physicians & Surgeons, Columbia University 1130 St Nicholas Ave
Tongyuan Li: Institute for Cancer Genetics, College of Physicians & Surgeons, Columbia University 1130 St Nicholas Ave
Shang-Jui Wang: Institute for Cancer Genetics, College of Physicians & Surgeons, Columbia University 1130 St Nicholas Ave
Tao Su: College of Physicians & Surgeons, Columbia University 630 West 168th Street
Hanina Hibshoosh: College of Physicians & Surgeons, Columbia University 630 West 168th Street
Richard Baer: Institute for Cancer Genetics, College of Physicians & Surgeons, Columbia University 1130 St Nicholas Ave
Wei Gu: Institute for Cancer Genetics, College of Physicians & Surgeons, Columbia University 1130 St Nicholas Ave

Nature, 2015, vol. 520, issue 7545, 57-62

Abstract: Abstract Although p53-mediated cell-cycle arrest, senescence and apoptosis serve as critical barriers to cancer development, emerging evidence suggests that the metabolic activities of p53 are also important. Here we show that p53 inhibits cystine uptake and sensitizes cells to ferroptosis, a non-apoptotic form of cell death, by repressing expression of SLC7A11, a key component of the cystine/glutamate antiporter. Notably, p533KR, an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, fully retains the ability to regulate SLC7A11 expression and induce ferroptosis upon reactive oxygen species (ROS)-induced stress. Analysis of mutant mice shows that these non-canonical p53 activities contribute to embryonic development and the lethality associated with loss of Mdm2. Moreover, SLC7A11 is highly expressed in human tumours, and its overexpression inhibits ROS-induced ferroptosis and abrogates p533KR-mediated tumour growth suppression in xenograft models. Our findings uncover a new mode of tumour suppression based on p53 regulation of cystine metabolism, ROS responses and ferroptosis.

Date: 2015
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DOI: 10.1038/nature14344

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