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      Ferroptosis, a new form of cell death: opportunities and challenges in cancer

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          Abstract

          Ferroptosis is a novel type of cell death with distinct properties and recognizing functions involved in physical conditions or various diseases including cancers. The fast-growing studies of ferroptosis in cancer have boosted a perspective for its usage in cancer therapeutics. Here, we review the current findings of ferroptosis regulation and especially focus on the function of ncRNAs in mediating the process of cell ferroptotic death and on how ferroptosis was in relation to other regulated cell deaths. Aberrant ferroptosis in diverse cancer types and tissues were summarized, and we elaborated recent data about the novel actors of some “conventional” drugs or natural compounds as ferroptosis inducers in cancer. Finally, we deliberate future orientation for ferroptosis in cancer cells and current unsettled issues, which may forward the speed of clinical use of ferroptosis induction in cancer treatment.

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          Most cited references113

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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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            Regulation of ferroptotic cancer cell death by GPX4.

            Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death. Copyright © 2014 Elsevier Inc. All rights reserved.
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              Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

              Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
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                Author and article information

                Contributors
                086-731-84327069 , duancjxy@mail.csu.edu.cn
                086-731-89753034 , bincsuxy@csu.edu.cn
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                29 March 2019
                29 March 2019
                2019
                : 12
                : 34
                Affiliations
                [1 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Department of Oncology, Xiangya Hospital, , Central South University, ; Changsha, 410008 People’s Republic of China
                [2 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Institute of Medical Sciences, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, , Central South University, ; Xiangya Road 87th, Changsha, 410008 Hunan People’s Republic of China
                [3 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Hunan Cancer Hospital, The Affiliated Tumor Hospital of Xiangya Medical College, , Central South University, ; Changsha, 410008 People’s Republic of China
                [4 ]ISNI 0000 0004 1757 7615, GRID grid.452223.0, Department of Thoracic Surgery, , Xiangya Hospital, Central South University, ; Changsha, 410008 People’s Republic of China
                [5 ]ISNI 0000 0004 1757 7615, GRID grid.452223.0, National Clinical Research Center for Geriatric Disorders, , Xiangya Hospital, Central South University, ; Changsha, People’s Republic of China
                Article
                720
                10.1186/s13045-019-0720-y
                6441206
                30925886
                c00e842e-3ef3-4133-978d-e84f78a51b13
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 11 December 2018
                : 11 March 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81572281
                Award ID: 81171841
                Award ID: 81200366
                Award ID: 81702278
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004735, Natural Science Foundation of Hunan Province;
                Award ID: 14JJ6004
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                ferroptosis,apoptosis,autophagy,ncrnas,cancers,p53
                Oncology & Radiotherapy
                ferroptosis, apoptosis, autophagy, ncrnas, cancers, p53

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