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      ROS homeostasis and metabolism: a critical liaison for cancer therapy

      review-article
      1 , 2 , 3 , * , 4 , *
      Experimental & Molecular Medicine
      Nature Publishing Group

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          Abstract

          Evidence indicates that hypoxia and oxidative stress can control metabolic reprogramming of cancer cells and other cells in tumor microenvironments and that the reprogrammed metabolic pathways in cancer tissue can also alter the redox balance. Thus, important steps toward developing novel cancer therapy approaches would be to identify and modulate critical biochemical nodes that are deregulated in cancer metabolism and determine if the therapeutic efficiency can be influenced by changes in redox homeostasis in cancer tissues. In this review, we will explore the molecular mechanisms responsible for the metabolic reprogramming of tumor microenvironments, the functional modulation of which may disrupt the effects of or may be disrupted by redox homeostasis modulating cancer therapy.

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          Most cited references112

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          p53 regulates mitochondrial respiration.

          The energy that sustains cancer cells is derived preferentially from glycolysis. This metabolic change, the Warburg effect, was one of the first alterations in cancer cells recognized as conferring a survival advantage. Here, we show that p53, one of the most frequently mutated genes in cancers, modulates the balance between the utilization of respiratory and glycolytic pathways. We identify Synthesis of Cytochrome c Oxidase 2 (SCO2) as the downstream mediator of this effect in mice and human cancer cell lines. SCO2 is critical for regulating the cytochrome c oxidase (COX) complex, the major site of oxygen utilization in the eukaryotic cell. Disruption of the SCO2 gene in human cancer cells with wild-type p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells. That SCO2 couples p53 to mitochondrial respiration provides a possible explanation for the Warburg effect and offers new clues as to how p53 might affect aging and metabolism.
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            Targeting lactate metabolism for cancer therapeutics.

            Lactate, once considered a waste product of glycolysis, has emerged as a critical regulator of cancer development, maintenance, and metastasis. Indeed, tumor lactate levels correlate with increased metastasis, tumor recurrence, and poor outcome. Lactate mediates cancer cell intrinsic effects on metabolism and has additional non-tumor cell autonomous effects that drive tumorigenesis. Tumor cells can metabolize lactate as an energy source and shuttle lactate to neighboring cancer cells, adjacent stroma, and vascular endothelial cells, which induces metabolic reprogramming. Lactate also plays roles in promoting tumor inflammation and in functioning as a signaling molecule that stimulates tumor angiogenesis. Here we review the mechanisms of lactate production and transport and highlight emerging evidence indicating that targeting lactate metabolism is a promising approach for cancer therapeutics.
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              Targeting metabolic transformation for cancer therapy.

              Cancer therapy has long relied on the rapid proliferation of tumour cells for effective treatment. However, the lack of specificity in this approach often leads to undesirable side effects. Many reports have described various 'metabolic transformation' events that enable cancer cells to survive, suggesting that metabolic pathways might be good targets. There are currently several drugs under development or in clinical trials that are based on specifically targeting the altered metabolic pathways of tumours. This Review highlights pathways against which there are already drugs in different stages of development and also discusses additional druggable targets.
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                Author and article information

                Journal
                Exp Mol Med
                Exp. Mol. Med
                Experimental & Molecular Medicine
                Nature Publishing Group
                1226-3613
                2092-6413
                November 2016
                04 November 2016
                1 November 2016
                : 48
                : 11
                : e269
                Affiliations
                [1 ]Cancer Control Team, Gachon University Gil Medical Center , Incheon, Republic of Korea
                [2 ]Department of Biochemistry, School of Medicine, Gachon University, Incheon, Republic of Korea
                [3 ]Department of Health Sciences and Technology, Gachon Advanced Institute for Health Science and Technology, Gachon University , Incheon, Republic of Korea
                [4 ]College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences , Daegu, Republic of Korea
                Author notes
                [* ]Department of Biochemistry, School of Medicine, Gachon University , 155 Gaetbeol-ro Yeonsu-Gu, Incheon 21999, Republic of Korea. E-mail: geretics@ 123456gachon.ac.kr
                [* ]College of Pharmacy, Kyungpook National University , 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea. E-mail: baejs@ 123456knu.ac.kr
                Article
                emm2016119
                10.1038/emm.2016.119
                5133371
                27811934
                a1000322-bfe5-427d-8f94-75ad36993bf5
                Copyright © 2016 The Author(s)

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

                History
                : 20 March 2016
                : 27 July 2016
                : 04 August 2016
                Categories
                Review

                Molecular medicine
                Molecular medicine

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