We hypothesize the existence of a p53-regulated nutrient-sensing metabolism checkpoint, in which dysregulation of key nutrients needed for oxidative metabolism drives accumulation of lipid peroxides. These lipid peroxides may enable activation of scavenging mechanisms that resolve the nutrient scarcity, induce alternative metabolic pathways that bypass the need for the scarce nutrients, and/or drive activation of ferroptotic cell death to eliminate cells damaged by nutrient scarcity. We suggest that each of these outputs can lead to a tumor suppressive phenotype, and that understanding the mechanisms that govern these processes is critical for understanding the evolution of human cancers and how they may be addressed with precision therapeutics. We focus here on the role of the p53 network in this checkpoint and its impact on tumor suppression. We have two major goals?to define how regulation of the mevalonate pathway by p53 alters sensitivity to ferroptosis in hepatocellular carcinomas and to define the regulatory mechanisms governing polyunsaturated fatty acid metabolism in lymphomas. Together, we suggest that these studies will define a critical new axis of p53-mediated tumor suppression and provide a new avenue for creation of precision cancer medicines.

Public Health Relevance

We are seeking to understand the intersection between the p53 network and ferroptosis, a form of regulated, non-apoptotic cell death discovered by the Stockwell Lab that has been suggested to participate in p53?s tumor suppression activity. We are examining two main hypotheses: first, that p53 regulates the mevalonate pathway, which drives resistance to ferroptosis through the biosynthesis of coenzyme Q10 and second, that p21 regulates sensitivity to ferroptosis. If successful, this research may illuminate new strategies for the treatment of specific patient tumors based on molecular properties, which is a goal of precision cancer research, and may provide new insights into how p53 suppresses tumorigenesis in lymphomas and hepatocellular carcinomas.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Columbia University (N.Y.)
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New York
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Otaka, Yukihiro; Rokudai, Susumu; Kaira, Kyoichi et al. (2017) STXBP4 Drives Tumor Growth and Is Associated with Poor Prognosis through PDGF Receptor Signaling in Lung Squamous Cell Carcinoma. Clin Cancer Res 23:3442-3452
Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Martín-Martín, Natalia et al. (2017) mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 547:109-113
Agmon, Eran; Stockwell, Brent R (2017) Lipid homeostasis and regulated cell death. Curr Opin Chem Biol 39:83-89
Kastenhuber, Edward R; Lowe, Scott W (2017) Putting p53 in Context. Cell 170:1062-1078
Levine, Arnold J; Berger, Shelley L (2017) The interplay between epigenetic changes and the p53 protein in stem cells. Genes Dev 31:1195-1201
Stockwell, Brent R; Friedmann Angeli, José Pedro; Bayir, Hülya et al. (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 171:273-285
Kribelbauer, Judith F; Laptenko, Oleg; Chen, Siying et al. (2017) Quantitative Analysis of the DNA Methylation Sensitivity of Transcription Factor Complexes. Cell Rep 19:2383-2395
Vabret, Nicolas; Bhardwaj, Nina; Greenbaum, Benjamin D (2017) Sequence-Specific Sensing of Nucleic Acids. Trends Immunol 38:53-65
Badal, Brateil; Solovyov, Alexander; Di Cecilia, Serena et al. (2017) Transcriptional dissection of melanoma identifies a high-risk subtype underlying TP53 family genes and epigenome deregulation. JCI Insight 2:
Hayano, M; Yang, W S; Corn, C K et al. (2016) Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ 23:270-8

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