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      Differential suitability of reactive oxygen species and the role of glutathione in regulating paradoxical behavior in gliomas: A mathematical perspective

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      Author(s): 1 , 2 , 1 , 2 , *
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      Publication date (Electronic):
      Journal: PLoS ONE
      Publisher: Public Library of Science

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          Abstract

          Manipulative strategies of ROS in cancer are often exhibited as changes in the redox and thiol ratio of the cells. Cellular responses to oxidative insults are generated in response to these changes which are triggered due to the rerouting of the metabolic framework to maintain survival under stress. However, mechanisms of these metabolic re-routing are not clearly understood and remained debatable. In the present work, we have designed a context-based dynamic metabolic model to establish that the coordinated functioning of glutathione peroxidase ( GTHP), glutathione oxidoreductase ( GTHO) and NADPH oxidase ( NOX) is crucial in determining cancerous transformation, specifically in gliomas. Further, we propose that the puzzling duality of ROS (represented by changes in h 2 o 2 in the present model) in exhibiting varying cellular fates can be determined by considering simultaneous changes in nadph/nadp + and gsh/gssg that occur during the reprogramming of metabolic reactions. This will be helpful in determining the pro-apoptotic or anti-apoptotic fate of gliomas and can be useful in designing effective pro-oxidant and/or anti-oxidant therapeutic approaches against gliomas.

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          Role of reactive oxygen species (ROS) in apoptosis induction.

          H U Simon, A. HAJ-YEHIA, F. Levi-Schaffer (2000)
          Reactive oxygen species (ROS) and mitochondria play an important role in apoptosis induction under both physiologic and pathologic conditions. Interestingly, mitochondria are both source and target of ROS. Cytochrome c release from mitochondria, that triggers caspase activation, appears to be largely mediated by direct or indirect ROS action. On the other hand, ROS have also anti-apoptotic effects. This review focuses on the role of ROS in the regulation of apoptosis, especially in inflammatory cells.
          Article 0 comments Cited 574 times – based on 0 reviews     Review now
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            Reactive oxygen species in cancer cells: live by the sword, die by the sword.

            Paul T. Schumacker (2006)
            Reactive oxygen species and tumor biology are intertwined in a complex web, making it difficult to understand which came first, whether oxidants are required for tumor cell growth, and whether oxidant stress can be exploited therapeutically. Evidence suggests that transformed cells use ROS signals to drive proliferation and other events required for tumor progression. This confers a state of increased basal oxidative stress, making them vulnerable to chemotherapeutic agents that further augment ROS generation or that weaken antioxidant defenses of the cell. In this respect, it appears that tumor cells may die by the same systems they require.
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              The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities.

              Jan Lewerenz, Sandra J Hewett, Ying Huang … (2013)
              The antiporter system x(c)(-) imports the amino acid cystine, the oxidized form of cysteine, into cells with a 1:1 counter-transport of glutamate. It is composed of a light chain, xCT, and a heavy chain, 4F2 heavy chain (4F2hc), and, thus, belongs to the family of heterodimeric amino acid transporters. Cysteine is the rate-limiting substrate for the important antioxidant glutathione (GSH) and, along with cystine, it also forms a key redox couple on its own. Glutamate is a major neurotransmitter in the central nervous system (CNS). By phylogenetic analysis, we show that system x(c)(-) is a rather evolutionarily new amino acid transport system. In addition, we summarize the current knowledge regarding the molecular mechanisms that regulate system x(c)(-), including the transcriptional regulation of the xCT light chain, posttranscriptional mechanisms, and pharmacological inhibitors of system x(c)(-). Moreover, the roles of system x(c)(-) in regulating GSH levels, the redox state of the extracellular cystine/cysteine redox couple, and extracellular glutamate levels are discussed. In vitro, glutamate-mediated system x(c)(-) inhibition leads to neuronal cell death, a paradigm called oxidative glutamate toxicity, which has successfully been used to identify neuroprotective compounds. In vivo, xCT has a rather restricted expression pattern with the highest levels in the CNS and parts of the immune system. System x(c)(-) is also present in the eye. Moreover, an elevated expression of xCT has been reported in cancer. We highlight the diverse roles of system x(c)(-) in the regulation of the immune response, in various aspects of cancer and in the eye and the CNS.
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                Author and article information

                Contributors
                Rupa Bhowmick: Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing – original draft
                Ram Rup Sarkar:
                ORCID: http://orcid.org/0000-0001-7115-163X
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Salvatore V. Pizzo: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 25 June 2020
                Publication date Collection: 2020
                Volume: 15
                Issue: 6
                Electronic Location Identifier: e0235204
                Affiliations
                [1 ] Chemical Engineering and Process Development Division, CSIR-National Chemical Laboratory, Pune, Maharashtra, India
                [2 ] Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, India
                Duke University School of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-7115-163X
                Article
                Publisher ID: PONE-D-19-27485
                DOI: 10.1371/journal.pone.0235204
                PMC ID: 7316271
                PubMed ID: 32584884
                SO-VID: ba02cc07-305b-4b5b-90d4-6ca5dd89d21a
                Copyright © © 2020 Bhowmick, Sarkar
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 11 October 2019
                Date accepted : 10 June 2020
                Page count
                Figures: 7, Tables: 2, Pages: 23
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001843, Science and Engineering Research Board;
                Award ID: EMR/2016/000516 Dated 19-12-2016
                Award Recipient :
                ORCID: http://orcid.org/0000-0001-7115-163X
                We thank SERB, Department of Science and Technology, Govt. of India (File No. EMR/2016/000516) and (DST/ICPS/EDA/2018), for providing financial support to Ram Rup Sarkar. Rupa Bhowmick acknowledges the Council of Scientific & Industrial Research (CSIR) for the Senior Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Elements
                Subject: Oxygen
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Neurological Tumors
                Subject: Glioma
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Neurological Tumors
                Subject: Glioma
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Peptides
                Subject: Glutathione
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Antioxidants
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Hypoxia
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Reactions
                Subject: Oxidation-Reduction Reactions
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Electrochemistry
                Subject: Oxidation-Reduction Reactions
                Subject: Medicine and Health Sciences
                Subject: Pharmaceutics
                Subject: Drug Therapy
                Subject: Antioxidant Therapy
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Enzymology
                Subject: Enzyme Chemistry
                Subject: Enzyme Metabolism
                Custom metadata
                Data Availability All relevant data are within the manuscript and its Supporting Information files.

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