title: Energy metabolism in neurodevelopment and medulloblastoma.
abstract: New, less toxic therapies are needed for medulloblastoma, the most common malignant brain tumor in children. Like many cancers, medulloblastomas demonstrate metabolic patterns that are markedly different from the surrounding non-neoplastic tissue and are highly organized to support tumor growth. Key aspects of medulloblastoma metabolism, including increased lipogenesis and aerobic glycolysis are derived from the metabolic programs of neural progenitors. During neural development, Sonic Hedgehog (Shh) signaling induces lipogenesis and aerobic glycolysis in proliferating progenitors to support rapid growth. Shh-regulated transcription induces specific genes, including hexokinase 2 (Hk2) and fatty acid synthase (FASN) that mediate these metabolic patterns. Medulloblastomas co-opt these developmentally-regulated patterns of metabolic gene expression for sustained tumor growth. Additionally, medulloblastomas limit protein translation through activation of eukaryotic elongation factor 2 kinase (eEF2K), to restrict energy expenditure. The activation of eEF2K reduces the need to generate ATP, enabling reduced dependence on oxidative phosphorylation and increased metabolism of glucose through aerobic glycolysis. Lipogenesis, aerobic glycolysis and restriction of protein translation operate in a network of metabolic processes that is integrated by adenosine monophosphate-activated protein kinase (AMPK) to maintain homeostasis. The homeostatic effect of AMPK has the potential to limit the impact of metabolically targeted interventions. Through combinatorial targeting of lipogenesis, glycolysis and eEF2K, however, this homeostatic effect may be overcome. We propose that combinatorial targeting of medulloblastoma metabolism may produce the synergies needed for effective anti-cancer therapy.
authors.affiliation: 1 Joint Department of Biomedical Engineering, NC State University and UNC Chapel Hill, Chapel Hill, NC 27599, USA ; 2 Department of Neurology, 3 Lineberger Comprehensive Cancer Center, 4 UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Tech
authors.affiliation: 1 Joint Department of Biomedical Engineering, NC State University and UNC Chapel Hill, Chapel Hill, NC 27599, USA ; 2 Department of Neurology, 3 Lineberger Comprehensive Cancer Center, 4 UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Gershon
keywords: Medulloblastoma; eukaryotic elongation factor 2 kinase (eEF2K); glycolysis; lipogenesis
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