Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation
| Autor: | Taylor Fish, Yisu Li, Katherine Tech, Marco A. Marra, Matthew G. Vander Heiden, Jessica Meidinger, Sarah C. Green, Andrey P. Tikunov, Andrew J. Mungall, Hamza Farooq, Yussanne Ma, A. Sorana Morrissy, Jeffrey M. Macdonald, Richard A. Moore, Michael D. Taylor, Steven J.M. Jones, Hedi Liu, Timothy R. Gershon |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Vander Heiden, Matthew G. |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Neurogenesis Blotting Western Pyruvate Kinase Biology PKM2 medicine.disease_cause Polymerase Chain Reaction Mass Spectrometry Article 03 medical and health sciences Mice Neural Stem Cells Cerebellum medicine Animals Humans Glycolysis Cerebellar Neoplasms Cell Proliferation Cell growth Metabolism Molecular biology Immunohistochemistry Mice Mutant Strains Cell biology Mice Inbred C57BL 030104 developmental biology Oncology Anaerobic glycolysis Carcinogenesis Pyruvate kinase Chromatography Liquid Medulloblastoma |
| Zdroj: | PMC |
| ISSN: | 1538-7445 |
| Popis: | Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNP) and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation, and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which postmitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM. Cancer Res; 77(12); 3217–30. ©2017 AACR. |
| Databáze: | OpenAIRE |
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