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      HIV-1 Envelope Protein gp120 Promotes Proliferation and the Activation of Glycolysis in Glioma Cell

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          Abstract

          Patients infected with human immunodeficiency virus (HIV) are more prone to developing cancers, including glioblastomas (GBMs). The median survival for HIV positive GBM patients is significantly shorter than for those who are uninfected, despite the fact that they receive the same treatments. The nature of the GBM–HIV association remains poorly understood. In this study, we analyzed the effect of the HIV envelope glycoprotein gp120 on GBM cell proliferation. Specifically, we performed cell cycle, western blot, protein synthesis and metabolomics analysis as well as ATP production and oxygen consumption assays to evaluate proliferation and metabolic pathways in primary human glioma cell line, U87, A172 cells and in the HIVgp120tg/GL261 mouse model. Glioma cells treated with gp120 (100 ng/mL for 7–10 days) showed higher proliferation rates and upregulation in the expression of enolase 2, hexokinase and glyceraldehyde-3-phosphate dehydrogenase when compared to untreated cells. Furthermore, we detected an increase in the activity of pyruvate kinase and a higher glycolytic index in gp120 treated cells. Gp120 treated GBM cells also showed heightened lipid and protein synthesis. Overall, we demonstrate that in glioma cells, the HIV envelope glycoprotein promotes proliferation and activation of glycolysis resulting in increased protein and lipid synthesis.

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            Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis.

            Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood. Using a metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.
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              Pyruvate kinase M2 is a phosphotyrosine-binding protein.

              Growth factors stimulate cells to take up excess nutrients and to use them for anabolic processes. The biochemical mechanism by which this is accomplished is not fully understood but it is initiated by phosphorylation of signalling proteins on tyrosine residues. Using a novel proteomic screen for phosphotyrosine-binding proteins, we have made the observation that an enzyme involved in glycolysis, the human M2 (fetal) isoform of pyruvate kinase (PKM2), binds directly and selectively to tyrosine-phosphorylated peptides. We show that binding of phosphotyrosine peptides to PKM2 results in release of the allosteric activator fructose-1,6-bisphosphate, leading to inhibition of PKM2 enzymatic activity. We also provide evidence that this regulation of PKM2 by phosphotyrosine signalling diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Collectively, our results indicate that expression of this phosphotyrosine-binding form of pyruvate kinase is critical for rapid growth in cancer cells.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                01 September 2018
                September 2018
                : 10
                : 9
                : 301
                Affiliations
                [1 ]Department of Biochemistry, Universidad Central del Caribe, School of Medicine, Ave. Laurel, Santa Juanita, Bayamon, PR 00956, USA; gabriel.valentin2@ 123456upr.edu (G.V.-G.); yuriy.kucheryavykh@ 123456uccaribe.edu (Y.V.K.); 115jperez@ 123456uccaribe.edu (J.P.); jescelica.ortiz@ 123456upr.edu (J.O.-R.)
                [2 ]Biomedical Proteomics Facility, Department of Microbiology and Immunology, Universidad Central del Caribe, School of Medicine, Ave. Laurel, Santa Juanita, Bayamon, PR 00956, USA; sheila_natalie@ 123456yahoo.com (S.L.); nawal.boukli@ 123456uccaribe.edu (N.B.)
                [3 ]Department of Biochemistry, University of Puerto Rico, School of Medicine, San Juan, PR 00936, USA; nataliya.chorna@ 123456upr.edu
                [4 ]Department of Physiology, Universidad Central del Caribe, School of Medicine, Ave. Laurel, Santa Juanita, Bayamon, PR 00956, USA; mikhail.inyushin@ 123456uccaribe.edu
                [5 ]Department of Physics, University of Puerto Rico, Río Piedras Campus, San Juan, PR 00931, USA; vmvimakarov@ 123456gmail.com
                [6 ]Department of Microbiology and Immunology, Universidad Central del Caribe, School of Medicine, Ave. Laurel, Santa Juanita, Bayamon, PR 00956, USA; anibal.valentin@ 123456uccaribe.edu
                [7 ]Department of Neurologic Surgery, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224, USA; quinones-hinojosa.alfredo@ 123456mayo.edu
                Author notes
                [* ]Correspondence: lilia.kucheryavykh@ 123456uccaribe.edu ; Tel.: +1-787-798-3001 (ext. 2037)
                Author information
                https://orcid.org/0000-0003-3253-7307
                https://orcid.org/0000-0002-5959-3184
                Article
                cancers-10-00301
                10.3390/cancers10090301
                6162763
                30200472
                2c93babc-8398-4e4b-a02e-c8fba69ff593
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 19 July 2018
                : 30 August 2018
                Categories
                Article

                glioma,hiv,gp120,glycolysis
                glioma, hiv, gp120, glycolysis

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