Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation
Ist Teil von
Cancer research (Chicago, Ill.), 2017-06, Vol.77 (12), p.3217-3230
Ort / Verlag
United States: American Association for Cancer Research, Inc
Erscheinungsjahr
2017
Quelle
MEDLINE
Beschreibungen/Notizen
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
(
) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting
(
), 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
deletion in CGNPs blocked all
expression.
-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation.
C-flux analysis showed that
deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux.
deletion accelerated tumor formation in medulloblastoma-prone
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.
.