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      Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells

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          Abstract

          The idea that conversion of glucose to ATP is an attractive target for cancer therapy has been supported in part by the observation that glucose deprivation induces apoptosis in rodent cells transduced with the proto-oncogene MYC, but not in the parental line. Here, we found that depletion of glucose killed normal human cells irrespective of induced MYC activity and by a mechanism different from apoptosis. However, depletion of glutamine, another major nutrient consumed by cancer cells, induced apoptosis depending on MYC activity. This apoptosis was preceded by depletion of the Krebs cycle intermediates, was prevented by two Krebs cycle substrates, but was unrelated to ATP synthesis or several other reported consequences of glutamine starvation. Our results suggest that the fate of normal human cells should be considered in evaluating nutrient deprivation as a strategy for cancer therapy, and that understanding how glutamine metabolism is linked to cell viability might provide new approaches for treatment of cancer.

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          Most cited references 57

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          On the origin of cancer cells.

           O WARBURG (1956)
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            RADIOAUTOGRAPHIC STUDIES OF CHOLINE INCORPORATION INTO PERIPHERAL NERVE MYELIN

            This radioautographic study was designed to localize the cytological sites involved in the incorporation of a lipid precursor into the myelin and the myelin-related cell of the peripheral nervous system. Both myelinating and fully myelinated cultures of rat dorsal root ganglia were exposed to a 30-min pulse of tritiated choline and either fixed immediately or allowed 6 or 48 hr of chase incubation before fixation. After Epon embedding, light and electron microscopic radioautograms were prepared with Ilford L-4 emulsion. Analysis of the pattern of choline incorporation into myelinating cultures indicated that radioactivity appeared all along the length of the internode, without there being a preferential site of initial incorporation. Light microscopic radioautograms of cultures at varying states of maturity were compared in order to determine the relative degree of myelin labeling. This analysis indicated that the myelin-Schwann cell unit in the fully myelinated cultures incorporated choline as actively as did this unit in the myelinating cultures. Because of technical difficulties, it was not possible to determine the precise localization of the incorporated radioactivity within the compact myelin. These data are related to recent biochemical studies indicating that the mature myelin of the central nervous system does incorporate a significant amount of lipid precursor under the appropriate experimental conditions. These observations support the concept that a significant amount of myelin-related metabolic activity occurs in mature tissue; this activity is considered part of an essential and continuous process of myelin maintenance and repair.
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              Transcriptional regulation and transformation by Myc proteins.

              Myc genes are key regulators of cell proliferation, and their deregulation contributes to the genesis of most human tumours. Recently, a wealth of data has shed new light on the biochemical functions of Myc proteins and on the mechanisms through which they function in cellular transformation.
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                Author and article information

                Journal
                J Cell Biol
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                2 July 2007
                : 178
                : 1
                : 93-105
                Affiliations
                [1 ]Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
                [2 ]G.W. Hooper Research Foundation, University of California at San Francisco, San Francisco, CA 94143
                [3 ]Institute of Molecular System Biology, ETH Zurich, 8093 Zurich, Switzerland
                [4 ]Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany
                Author notes

                Correspondence to Yuri Lazebnik: lazebnik@ 123456cshl.edu

                Article
                200703099
                10.1083/jcb.200703099
                2064426
                17606868
                Copyright © 2007, The Rockefeller University Press
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                Research Articles
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                Cell biology

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