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Global Metabolic Profiling of Infection by an Oncogenic Virus: KSHV Induces and Requires Lipogenesis for Survival of Latent Infection

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      Abstract

      Like cancer cells, virally infected cells have dramatically altered metabolic requirements. We analyzed global metabolic changes induced by latent infection with an oncogenic virus, Kaposi's Sarcoma-associated herpesvirus (KSHV). KSHV is the etiologic agent of Kaposi's Sarcoma (KS), the most common tumor of AIDS patients. Approximately one-third of the nearly 200 measured metabolites were altered following latent infection of endothelial cells by KSHV, including many metabolites of anabolic pathways common to most cancer cells. KSHV induced pathways that are commonly altered in cancer cells including glycolysis, the pentose phosphate pathway, amino acid production and fatty acid synthesis. Interestingly, over half of the detectable long chain fatty acids detected in our screen were significantly increased by latent KSHV infection. KSHV infection leads to the elevation of metabolites involved in the synthesis of fatty acids, not degradation from phospholipids, and leads to increased lipid droplet organelle formation in the infected cells. Fatty acid synthesis is required for the survival of latently infected endothelial cells, as inhibition of key enzymes in this pathway led to apoptosis of infected cells. Addition of palmitic acid to latently infected cells treated with a fatty acid synthesis inhibitor protected the cells from death indicating that the products of this pathway are essential. Our metabolomic analysis of KSHV-infected cells provides insight as to how oncogenic viruses can induce metabolic alterations common to cancer cells. Furthermore, this analysis raises the possibility that metabolic pathways may provide novel therapeutic targets for the inhibition of latent KSHV infection and ultimately KS tumors.

      Author Summary

      In recent years there has been a resurgence in the study of metabolic changes in tumor cells. To determine if an oncogenic virus alters similar metabolic pathways as cancer cells, we measured the levels of a large number of metabolites in endothelial cells infected with Kaposi?s Sarcoma-associated herpesvirus (KSHV). KSHV is the etiologic agent of Kaposi's Sarcoma (KS), the most common tumor of AIDS patients world wide. Latent KSHV infection of endothelial cells altered a significant proportion of the host cell metabolites. Many metabolic pathways that are altered in most tumor cells were also altered by KSHV. In particular, KSHV upregulated fatty acid synthesis, a pathway that provides membrane material and metabolites critical for cell proliferation. Inhibitors of fatty acid synthesis kill many types of tumor cells and we found that these inhibitors led to death of cells latently infected with KSHV. In summary, we found that a directly oncogenic virus alters the same host metabolic pathways that are dysregulated in many cancer cells and that inhibition of these pathways can be used to kill off infected cells, thereby providing novel therapeutic targets for KSHV and ultimately KS tumors.

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      Most cited references 37

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        Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis.

        There is a renewed interest in the ultimate role of fatty acid synthase (FASN)--a key lipogenic enzyme catalysing the terminal steps in the de novo biogenesis of fatty acids--in cancer pathogenesis. Tumour-associated FASN, by conferring growth and survival advantages rather than functioning as an anabolic energy-storage pathway, appears to necessarily accompany the natural history of most human cancers. A recent identification of cross-talk between FASN and well-established cancer-controlling networks begins to delineate the oncogenic nature of FASN-driven lipogenesis. FASN, a nearly-universal druggable target in many human carcinomas and their precursor lesions, offers new therapeutic opportunities for metabolically treating and preventing cancer.
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          Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis.

          The protease responsible for the cleavage of poly(ADP-ribose) polymerase and necessary for apoptosis has been purified and characterized. This enzyme, named apopain, is composed of two subunits of relative molecular mass (M(r)) 17K and 12K that are derived from a common proenzyme identified as CPP32. This proenzyme is related to interleukin-1 beta-converting enzyme (ICE) and CED-3, the product of a gene required for programmed cell death in Caenorhabditis elegans. A potent peptide aldehyde inhibitor has been developed and shown to prevent apoptotic events in vitro, suggesting that apopain/CPP32 is important for the initiation of apoptotic cell death.
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            Author and article information

            Affiliations
            [1 ]Department of Microbiology, University of Washington, Seattle, Washington, United States of America
            [2 ]Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, United States of America
            University of Texas Southwestern Medical School, United States of America
            Author notes

            The authors have declared that no competing interests exist.

            Conceived and designed the experiments: TD ELS ML. Performed the experiments: TD ELS RC. Analyzed the data: TD ELS ML. Wrote the paper: TD ELS ML.

            Contributors
            Role: Editor
            Journal
            PLoS Pathog
            PLoS Pathog
            plos
            plospath
            PLoS Pathogens
            Public Library of Science (San Francisco, USA )
            1553-7366
            1553-7374
            August 2012
            August 2012
            16 August 2012
            : 8
            : 8
            3420960
            22916018
            PPATHOGENS-D-12-00582
            10.1371/journal.ppat.1002866
            (Editor)

            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.

            Counts
            Pages: 11
            Funding
            TD and ELS were supported in part by a Public Health Service, National Research Service Award (T32GM07270) from the National institute of General Medical Sciences. ML is supported by grants from the NCI (RO1CA097934) and from the NIDCR (PO1E021954). The funders had no role in study design data collection and analysis, decision to publish or preparation of the manuscript.
            Categories
            Research Article
            Biology
            Microbiology
            Host-Pathogen Interaction
            Microbial Metabolism
            Virology
            Proteomics

            Infectious disease & Microbiology

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