Ferroptosis as a p53-mediated activity during tumour suppression

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. p53 suppresses expression of SLC7A11, a key component of the cystine/glutamate amino acid transport machinery, leading to inhibition of cystine uptake and promoting ferroptosis, an iron-dependent form of cell death. The tumour suppressor activity of the transcription factor p53 is typically thought to reflect its ability to induce cell cycle arrest, apoptosis or senescence in response to cellular stress, but there is emerging evidence for other activities of p53. Here Wei Gu and colleagues show that a metabolic target of p53 can also contribute to its tumour suppressor activity. In particular, they find that p53 suppresses expression of SLC7A11, a key component of the cystine/glutamate amino acid transport machinery. This leads to inhibition of cystine uptake and promotes ferroptosis, an iron-dependent form of cell death. This previously unrecognized function of p53 seems to be important in tumour suppression, particularly when other pathways are inoperative.