title: Ferroptosis as a p53-mediated activity during tumour suppression.
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, p53(3KR), 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 p53(3KR)-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.
authors: Institute for Cancer Genetics, College of Physicians &Surgeons, Columbia University 1130 St Nicholas Ave, New York, New York 10032, USA.
authors: Le
authors: L
authors: Jiang
authors: Institute for Cancer Genetics, College of Physicians &Surgeons, Columbia University 1130 St Nicholas Ave, New York, New York 10032, USA.
authors: Ning
authors: N
authors: Kon
authors: Institute for Cancer Genetics, College of Physicians &Surgeons, Columbia University 1130 St Nicholas Ave, New York, New York 10032, USA.
authors: Tongyuan
authors: T
authors: Li
authors: Institute for Cancer Genetics, College of Physicians &Surgeons, Columbia University 1130 St Nicholas Ave, New York, New York 10032, USA.
authors: Shang-Jui
authors: SJ
authors: Wang
authors: 1] Department of Pathology and Cell Biology, College of Physicians &Surgeons, Columbia University 630 West 168th Street, New York, New York 10032, USA [2] Herbert Irving Comprehensive Cancer Center, College of Physicians &Surgeons, Columbia University 1130 St Nicholas Ave, New York, New York 10032, USA.
authors: Tao
authors: T
authors: Su
authors: 1] Department of Pathology and Cell Biology, College of Physicians &Surgeons, Columbia University 630 West 168th Street, New York, New York 10032, USA [2] Herbert Irving Comprehensive Cancer Center, College of Physicians &Surgeons, Columbia University 1130 St Nicholas Ave, New York, New York 10032, USA.
authors: Hanina
authors: H
authors: Hibshoosh
authors: 1] Institute for Cancer Genetics, College of Physicians &Surgeons, Columbia University 1130 St Nicholas Ave, New York, New York 10032, USA [2] Department of Pathology and Cell Biology, College of Physicians &Surgeons, Columbia University 630 West 168th Street, New York, New York 10032, USA [3] Herbert Irving Comprehensive Cancer Center, College of Physicians &Surgeons, Columbia University 1130 St Nicholas Ave, New York, New York 10032, USA.
authors: Richard
authors: R
authors: Baer
authors: 1] Institute for Cancer Genetics, College of Physicians &Surgeons, Columbia University 1130 St Nicholas Ave, New York, New York 10032, USA [2] Department of Pathology and Cell Biology, College of Physicians &Surgeons, Columbia University 630 West 168th Street, New York, New York 10032, USA [3] Herbert Irving Comprehensive Cancer Center, College of Physicians &Surgeons, Columbia University 1130 St Nicholas Ave, New York, New York 10032, USA.
authors: Wei
authors: W
authors: Gu
mesh_terms: D027182:Amino Acid Transport System y+ / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D016923:Cell Death; D003553:Cystine / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D047108:Embryonic Development; D006801:Humans; D007501:Iron / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress; D051736:Proto-Oncogene Proteins c-mdm2 / Q000172:deficiency / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013379:Substrate Specificity; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D027182:Amino Acid Transport System y+; D017382:Reactive Oxygen Species; C118895:SLC7A11 protein, human; D016159:Tumor Suppressor Protein p53; D003553:Cystine; D007501:Iron; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2