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      Mitochondrial recoupling: a novel therapeutic strategy for cancer?

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          Abstract

          Recent findings link metabolic transformation of cancer cells to aberrant functions of mitochondrial uncoupling proteins (UCPs). By inducing proton leak, UCPs interfere with mitochondrial synthesis of adenosine 5′-triphosphate, which is also a key determinant of glycolytic pathways. In addition, UCP suppress the generation of superoxide, a byproduct of mitochondrial electron transport and a major source of oxidative stress. The near ubiquitous UCP2 becomes highly abundant in some cancers and may advance metabolic reprogramming, further disrupt tumour suppression, and promote chemoresistance. Here we review current evidence to suggest that inhibition of mitochondrial uncoupling may eliminate these responses and reveal novel anti-cancer strategies.

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          Most cited references27

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          Radical causes of cancer.

          Free radicals are ubiquitous in our body and are generated by normal physiological processes, including aerobic metabolism and inflammatory responses, to eliminate invading pathogenic microorganisms. Because free radicals can also inflict cellular damage, several defences have evolved both to protect our cells from radicals--such as antioxidant scavengers and enzymes--and to repair DNA damage. Understanding the association between chronic inflammation and cancer provides insights into the molecular mechanisms involved. In particular, we highlight the interaction between nitric oxide and p53 as a crucial pathway in inflammatory-mediated carcinogenesis.
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            Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production.

            The gene Ucp2 is a member of a family of genes found in animals and plants, encoding a protein homologous to the brown fat uncoupling protein Ucp1 (refs 1-3). As Ucp2 is widely expressed in mammalian tissues, uncouples respiration and resides within a region of genetic linkage to obesity, a role in energy dissipation has been proposed. We demonstrate here, however, that mice lacking Ucp2 following targeted gene disruption are not obese and have a normal response to cold exposure or high-fat diet. Expression of Ucp2 is robust in spleen, lung and isolated macrophages, suggesting a role for Ucp2 in immunity or inflammatory responsiveness. We investigated the response to infection with Toxoplasma gondii in Ucp2-/- mice, and found that they are completely resistant to infection, in contrast with the lethality observed in wild-type littermates. Parasitic cysts and inflammation sites in brain were significantly reduced in Ucp2-/- mice (63% decrease, P<0.04). Macrophages from Ucp2-/- mice generated more reactive oxygen species than wild-type mice (80% increase, P<0.001) in response to T. gondii, and had a fivefold greater toxoplasmacidal activity in vitro compared with wild-type mice (P<0.001 ), which was absent in the presence of a quencher of reactive oxygen species (ROS). Our results indicate a role for Ucp2 in the limitation of ROS and macrophage-mediated immunity.
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              Superoxide and hydrogen peroxide in relation to mammalian cell proliferation.

              R. Burdon (1995)
              A wide variety of normal and malignant cell types generate and release superoxide or hydrogen peroxide in vitro either in response to specific cytokine/growth factor stimulus or constitutively in the case of tumour cells. These species at submicromolar levels appear to act as novel intra and intercellular "messengers" capable of promoting growth responses in culture. The mechanisms may involve direct interaction with specific receptors or oxidation of growth signal transduction molecules such as protein kinases, protein phosphatases, transcription factors, or transcription factor inhibitors. It is also possible that hydrogen peroxide may modulate the redox state and activity of these important signal transduction proteins indirectly through changes in cellular levels of GSH and GSSG. Critical balances appear to exist in relation to cell proliferation on one hand and lipid peroxidation and cell death on the other. Progression to a more prooxidant state whilst initially leading to enhanced proliferative responses results subsequently in increased cell death.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                09 August 2011
                28 June 2011
                : 105
                : 4
                : 469-474
                Affiliations
                [1 ]simpleDepartment of Medicine, VA Boston Healthcare System and Brigham and Women's Hospital, Harvard Medical School , 150 S Huntington Avenue, Room A6-46, Boston, MA 02130, USA
                [2 ]simpleLiver Research Center, Department of Medicine, Rhode Island Hospital and Alpert School of Medicine, Brown University , Providence, RI 02903, USA
                [3 ]simpleLiver Clinic, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02215, USA
                Author notes
                Article
                bjc2011245
                10.1038/bjc.2011.245
                3170958
                21712825
                01534a30-459d-4eea-b6f7-fe76001611d7
                Copyright © 2011 Cancer Research UK
                History
                : 16 February 2011
                : 28 April 2011
                : 08 June 2011
                Categories
                Minireview

                Oncology & Radiotherapy
                aerobic glycolysis,ucp2,uncoupling proteins,p53,oxidative stress,metabolic reprogramming

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