Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation
Author(s)
Tech, Katherine; Tikunov, Andrey P.; Farooq, Hamza; Morrissy, A. Sorana; Meidinger, Jessica; Fish, Taylor; Green, Sarah C.; Liu, Hedi; Li, Yisu; Mungall, Andrew J.; Moore, Richard A.; Ma, Yussanne; Jones, Steven J.M.; Marra, Marco A.; Vander Heiden, Matthew G.; Taylor, Michael D.; Macdonald, Jeffrey M.; Gershon, Timothy R.; ... Show more Show less![Thumbnail](/bitstream/handle/1721.1/116953/nihms871446.pdf.jpg?sequence=6&isAllowed=y)
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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.
Date issued
2017-05Department
Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MITJournal
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Citation
Tech, Katherine et al. “Pyruvate Kinase Inhibits Proliferation During Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation.” Cancer Research 77, 12 (May 2017): 3217–3230 © 2017 American Association for Cancer Research
Version: Author's final manuscript
ISSN
0008-5472
1538-7445