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    The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-03-14
    Description: Many tumour cells have elevated rates of glucose uptake but reduced rates of oxidative phosphorylation. This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis. Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase. Here we use short hairpin RNA to knockdown pyruvate kinase M2 expression in human cancer cell lines and replace it with pyruvate kinase M1. Switching pyruvate kinase expression to the M1 (adult) isoform leads to reversal of the Warburg effect, as judged by reduced lactate production and increased oxygen consumption, and this correlates with a reduced ability to form tumours in nude mouse xenografts. These results demonstrate that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Christofk, Heather R -- Vander Heiden, Matthew G -- Harris, Marian H -- Ramanathan, Arvind -- Gerszten, Robert E -- Wei, Ru -- Fleming, Mark D -- Schreiber, Stuart L -- Cantley, Lewis C -- R01 GM056203/GM/NIGMS NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Mar 13;452(7184):230-3. doi: 10.1038/nature06734.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18337823" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing/*genetics ; Animals ; Cell Line, Tumor ; Cell Proliferation ; Fructosediphosphates/metabolism ; Gene Expression Regulation, Neoplastic ; Glycolysis ; Humans ; Lactic Acid/metabolism ; Lung Neoplasms/genetics/metabolism/pathology ; Male ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Neoplasms/enzymology/genetics/*metabolism/*pathology ; Oxidative Phosphorylation ; Oxygen Consumption ; Pyruvate Kinase/*genetics/*metabolism ; Pyruvic Acid/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-05-15
    Description: Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810415/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810415/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Commisso, Cosimo -- Davidson, Shawn M -- Soydaner-Azeloglu, Rengin G -- Parker, Seth J -- Kamphorst, Jurre J -- Hackett, Sean -- Grabocka, Elda -- Nofal, Michel -- Drebin, Jeffrey A -- Thompson, Craig B -- Rabinowitz, Joshua D -- Metallo, Christian M -- Vander Heiden, Matthew G -- Bar-Sagi, Dafna -- 5 P30CA016087-32/CA/NCI NIH HHS/ -- P01 CA104838/CA/NCI NIH HHS/ -- P01 CA117969/CA/NCI NIH HHS/ -- P01-CA117969/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30-CA14051-39/CA/NCI NIH HHS/ -- R01 CA055360/CA/NCI NIH HHS/ -- R01 CA105463/CA/NCI NIH HHS/ -- R01 CA163591/CA/NCI NIH HHS/ -- R01CA055360/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2013 May 30;497(7451):633-7. doi: 10.1038/nature12138. Epub 2013 May 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23665962" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acids/*metabolism ; Animals ; Biological Transport ; Carbon/metabolism ; Cell Line, Transformed ; Cell Line, Tumor ; Cell Proliferation ; *Cell Transformation, Neoplastic/genetics ; Disease Models, Animal ; Female ; Glutamine/metabolism ; Mice ; Mice, Nude ; NIH 3T3 Cells ; Oncogene Protein p21(ras)/genetics/*metabolism ; Pancreatic Neoplasms/genetics/*metabolism/*pathology ; *Pinocytosis ; Proteolysis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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