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      The p53 Tumor Suppressor in the Control of Metabolism and Ferroptosis

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          Abstract

          The p53 tumor suppressor continues to be distinguished as the most frequently mutated gene in human cancer. It is widely believed that the ability of p53 to induce senescence and programmed cell death underlies the tumor suppressor functions of p53. However, p53 has a number of other functions that recent data strongly implicate in tumor suppression, particularly with regard to the control of metabolism and ferroptosis (iron- and lipid-peroxide-mediated cell death) by p53. As reviewed here, the roles of p53 in the control of metabolism and ferroptosis are complex. Wild-type (WT) p53 negatively regulates lipid synthesis and glycolysis in normal and tumor cells, and positively regulates oxidative phosphorylation and lipid catabolism. Mutant p53 in tumor cells does the converse, positively regulating lipid synthesis and glycolysis. The role of p53 in ferroptosis is even more complex: in normal tissues, WT p53 appears to positively regulate ferroptosis, and this pathway appears to play a role in the ability of basal, unstressed p53 to suppress tumor initiation and development. In tumors, other regulators of ferroptosis supersede p53’s role, and WT p53 appears to play a limited role; instead, mutant p53 sensitizes tumor cells to ferroptosis. By clearly elucidating the roles of WT and mutant p53 in metabolism and ferroptosis, and establishing these roles in tumor suppression, emerging research promises to yield new therapeutic avenues for cancer and metabolic diseases.

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          Most cited references59

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          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Ferroptosis: an iron-dependent form of nonapoptotic cell death.

            Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

              Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                11 April 2018
                2018
                : 9
                : 124
                Affiliations
                [1] 1Program in Molecular and Cellular Oncogenesis, The Wistar Institute , Philadelphia, PA, United States
                [2] 2Graduate Group in Biochemistry and Molecular Biophysics, The Perelman School of Medicine, The University of Pennsylvania , Philadelphia, PA, United States
                [3] 3Department of Internal Medicine, School of Medicine, Washington University in St. Louis , St Louis, MO, United States
                Author notes

                Edited by: Haim Werner, Tel Aviv University, Israel

                Reviewed by: Catherine Pellat-Deceunynck, Centre national de la recherche scientifique (CNRS), France; Osnat Ashur-Fabian, Tel Aviv University, Israel

                *Correspondence: Maureen E. Murphy, mmurphy@ 123456wistar.org

                Specialty section: This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2018.00124
                5904197
                29695998
                6015eee0-fe0d-4067-8466-24e1ad1ad6c5
                Copyright © 2018 Gnanapradeepan, Basu, Barnoud, Budina-Kolomets, Kung and Murphy.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 25 January 2018
                : 12 March 2018
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 57, Pages: 7, Words: 5589
                Funding
                Funded by: National Cancer Institute 10.13039/100000054
                Award ID: R01 CA102184, R01 CA201430, T32 CA009171, TL1TR002344
                Categories
                Endocrinology
                Review

                Endocrinology & Diabetes
                p53,metabolism,ferroptosis,apoptosis,tumor suppressor
                Endocrinology & Diabetes
                p53, metabolism, ferroptosis, apoptosis, tumor suppressor

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