%0 Journal Article
%T Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma
%A Timothy R Gershon
%A Andrew J Crowther
%A Andrey Tikunov
%A Idoia Garcia
%A Ryan Annis
%A Hong Yuan
%A C Miller
%A Jeffrey Macdonald
%A James Olson
%A Mohanish Deshmukh
%J Cancer & Metabolism
%D 2013
%I BioMed Central
%R 10.1186/2049-3002-1-2
%X 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.See commentary article:http://www.biomedcentral.com/1741-7007/11/3 webciteAerobic glycolysis, the metabolism of glucose to lactate despite the availability of oxygen, is observed in diverse cancers, a phenomenon known as the Warburg effect [1,2]. Indeed, many cancers, including brain tumors, demonstrate increased glucose utilization, suggesting that glycolytic metabolism may confer a selective advantage [3,4]. Less is known about metabolic adaptations during development. Examining these adaptations is important because metabolic patterns that support cancerous growth may
%K Warburg effect
%K Aerobic glycolysis
%K Medulloblastoma
%K Smoothened
%K Brain tumor
%K Cerebellum
%U http://www.cancerandmetabolism.com/content/1/1/2