Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma
1 Department of Neurology, University of North Carolina, Chapel Hill, NC, 27599, USA
2 Neuroscience Center, University of North Carolina, Chapel Hill, NC, 27599, USA
3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA
4 Joint Department of Biomedical Engineering, NC State University and UNC Chapel Hill, Chapel Hill, NC, 27599, USA
5 Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC, 27599, USA
6 Department of Radiology, University of North Carolina, Chapel Hill, NC, 27599, USA
7 Department of Pathology, Division of Neuropathology, University of North Carolina, Chapel Hill, NC, 27599, USA
8 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
9 UNC School of Medicine, 170 Manning Drive CB7025, Chapel Hill, NC, 27599, USA
Cancer & Metabolism 2013, 1:2 doi:10.1186/2049-3002-1-2Published: 23 January 2013
While aerobic glycolysis is linked to unconstrained proliferation in cancer, less is known about its physiological role. Why this metabolic program that promotes tumor growth is preserved in the genome has thus been unresolved. We tested the hypothesis that aerobic glycolysis derives from developmental processes that regulate rapid proliferation.
We performed an integrated analysis of metabolism and gene expression in cerebellar granule neuron progenitors (CGNPs) with and without Sonic Hedgehog (Shh), their endogenous mitogen. Because our analysis highlighted Hexokinase-2 (Hk2) as a key metabolic regulator induced by Shh, we studied the effect of conditional genetic Hk2 deletion in CGNP development. We then crossed Hk2 conditional knockout mice with transgenic SmoM2 mice that develop spontaneous medulloblastoma and determined changes in SmoM2-driven tumorigenesis.
We show that Shh and phosphoinositide 3-kinase (PI3K) signaling combine to induce an Hk2-dependent glycolytic phenotype in CGNPs. This phenotype is recapitulated in medulloblastoma, a malignant tumor of CGNP origin. Importantly, cre-mediated ablation of Hk2 abrogated aerobic glycolysis, disrupting CGNP development and Smoothened-induced tumorigenesis. Comparing tumorigenesis in medulloblastoma-prone SmoM2 mice with and without functional Hk2, we demonstrate that loss of aerobic glycolysis reduces the aggressiveness of medulloblastoma, causing tumors to grow as indolent lesions and allowing long-term survival of tumor bearing mice.
Our investigations demonstrate that aerobic glycolysis in cancer derives from developmental mechanisms that persist in tumorigenesis. Moreover, we demonstrate in a primary tumor model the anti-cancer potential of blocking aerobic glycolysis by targeting Hk2.