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      An invertebrate Warburg effect: a shrimp virus achieves successful replication by altering the host metabolome via the PI3K-Akt-mTOR pathway.

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          Abstract

          In this study, we used a systems biology approach to investigate changes in the proteome and metabolome of shrimp hemocytes infected by the invertebrate virus WSSV (white spot syndrome virus) at the viral genome replication stage (12 hpi) and the late stage (24 hpi). At 12 hpi, but not at 24 hpi, there was significant up-regulation of the markers of several metabolic pathways associated with the vertebrate Warburg effect (or aerobic glycolysis), including glycolysis, the pentose phosphate pathway, nucleotide biosynthesis, glutaminolysis and amino acid biosynthesis. We show that the PI3K-Akt-mTOR pathway was of central importance in triggering this WSSV-induced Warburg effect. Although dsRNA silencing of the mTORC1 activator Rheb had only a relatively minor impact on WSSV replication, in vivo chemical inhibition of Akt, mTORC1 and mTORC2 suppressed the WSSV-induced Warburg effect and reduced both WSSV gene expression and viral genome replication. When the Warburg effect was suppressed by pretreatment with the mTOR inhibitor Torin 1, even the subsequent up-regulation of the TCA cycle was insufficient to satisfy the virus's requirements for energy and macromolecular precursors. The WSSV-induced Warburg effect therefore appears to be essential for successful viral replication.

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          Understanding the Warburg effect: the metabolic requirements of cell proliferation.

          In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5'-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.
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            On the origin of cancer cells.

             O WARBURG (1956)
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              Upstream and downstream of mTOR.

              The evolutionarily conserved checkpoint protein kinase, TOR (target of rapamycin), has emerged as a major effector of cell growth and proliferation via the regulation of protein synthesis. Work in the last decade clearly demonstrates that TOR controls protein synthesis through a stunning number of downstream targets. Some of the targets are phosphorylated directly by TOR, but many are phosphorylated indirectly. In this review, we summarize some recent developments in this fast-evolving field. We describe both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis. We also summarize the roles of mTOR in the control of cell growth and proliferation, as well as its relevance to cancer and synaptic plasticity.
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                Author and article information

                Journal
                PLoS Pathog.
                PLoS pathogens
                Public Library of Science (PLoS)
                1553-7374
                1553-7366
                Jun 2014
                : 10
                : 6
                Affiliations
                [1 ] Institute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
                [2 ] Institute of Zoology, College of Life Science, National Taiwan University, Taipei, Taiwan.
                [3 ] Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan; Center for Systems Biology, National Taiwan University, Taipei, Taiwan.
                [4 ] Core Facilities for Protein Structural Analysis, Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
                [5 ] Academia Sinica Common Mass Spectrometry Facilities at Institute of Biological Chemistry, Taipei, Taiwan.
                [6 ] Department of Life Science, College of Life Science, National Taiwan University, Taipei, Taiwan.
                [7 ] Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan; Core Facilities for Protein Structural Analysis, Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
                [8 ] Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
                [9 ] Institute of Zoology, College of Life Science, National Taiwan University, Taipei, Taiwan; Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan.
                Article
                PPATHOGENS-D-13-02598
                10.1371/journal.ppat.1004196
                4055789

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