Ferroptosis as a p53-mediated activity during tumour suppression

By Le Jiang, N. Kon, Tongyuan Li, Shang-Jui Wang, T. Su, H. Hibshoosh, R. Baer, W. Gu. Nature, 2015

3,011 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/f19ad491d28c86cf402e37efcd138a460a10ab4e

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Citations in the corpus

Role of Glutathione in Cancer: From Mechanisms to Therapies (2020, background): “Moreover, NADPH production by the oxidative branch of the PPP is increased in many types of cancer cells [32,53].”
Ferroptosis: mechanisms and links with diseases (2021, background): “The function of p53 (3KR) tumorigenesis suppression is realized by inhibiting SLC7A11 expression and inducing ferroptosis in xenograft models.(102) Similarly, BRCA1 associated protein 1 (BAP1) and OTU deubiquitinase, ubiquitin aldehyde-binding 1 (OTUB1), both involved in tumor regulation, can contro”
Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, background): “Mechanistically, activation of p53 substantially reduces cystine absorption by system XC, which in turn inhibits intracellular GSH production, hence modulating the proliferation of tumor cells [130, 131].”
Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis (2016, background): “S3), which has itself been linked to ferroptosis regulation (48, 49), providing an avenue for future exploration.”
The cell biology of ferroptosis (2024, neutral): “The tumour suppressor protein p53 also seems to be capable of either promoting or inhibiting ferroptosis through various molecular mechanisms, depending on the cell type and even on the nature of the ferroptosis-inducing stimulus 6,117,164,193”
Emerging mechanisms and disease relevance of ferroptosis (2020, background): “Indeed, p53 (3KR: K117R+K161R+K162R), an acetylation-defective mutant that fails to induce cell cycle arrest, senescence, and apoptosis, retains the ability to suppress tumor formation in vivo and to promote ferroptosis through metabolic regulation, including downregulation of SLC7A11, a key compone”
The Tumor Suppressor Protein p53 and the Ferroptosis Network (2018, neutral): “Mechanistically, ATF4 and p53 have been reported to promote or inhibit SLC7A11 gene transcription in ferroptosis, respectively [12,35].”
Ferroptosis: process and function (2016, background): “This tumor suppressor function of p53 is dependent on the induction of ferroptosis.(27) Ferroptosis also mediates hyperactive p53 signaling in the promotion of embryonic lethality.”
Activation of the p62-Keap1-NRF2 Pathway Protects against Ferroptosis in Hepatocellular Carcinoma Cells (2015, background): “p53 (especially acetylation-defective mutant p53) is responsible for the inhibition of SLC711A expression in ferroptosis.(23) Suppression of SLC7A11 leads to GSH depletion and increased ferroptosis following erastin treatment.”
Ferroptosis: Death by Lipid Peroxidation. (2016, background): “A recent study reported that p53 can activate ferroptosis by suppressing the expression of SLC7A11, a component of system xc [75].”
Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, neutral): “The most commonly mutated tumor suppressor protein, p53, suppresses solute carrier family 7 member 11 (SLC7A11) expression (Jiang et al., 2015), which is one of the two genes that encode the components of system xc .”