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Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation.
- Source :
-
Cancer research [Cancer Res] 2017 Jun 15; Vol. 77 (12), pp. 3217-3230. Date of Electronic Publication: 2017 May 17. - Publication Year :
- 2017
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Abstract
- 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. <superscript>13</superscript> C-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 .<br /> (©2017 American Association for Cancer Research.)
- Subjects :
- Animals
Blotting, Western
Cell Proliferation
Cerebellar Neoplasms pathology
Chromatography, Liquid
Humans
Immunohistochemistry
Mass Spectrometry
Medulloblastoma pathology
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Neural Stem Cells pathology
Polymerase Chain Reaction
Cerebellar Neoplasms enzymology
Cerebellum enzymology
Medulloblastoma enzymology
Neural Stem Cells enzymology
Neurogenesis physiology
Pyruvate Kinase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 77
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 28515149
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-16-3304