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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
Cancer research (Chicago, Ill.), 06/2017, Volume: 77, Issue: 12Journal Article
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. .
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