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.

Keywords: Medulloblastoma; eukaryotic elongation factor 2 kinase (eEF2K); glycolysis; lipogenesis.

Figure 1

Proliferating cells must balance energy demands with biosynthesis requirements. During rapid growth, cells increase aerobic glycolysis to generate intermediates for biosynthetic pathways, such as lipogenesis, and to maintain low ATP production. Likewise, phosphorylated eEF2K actively reduces global protein translation to conserve energy and redirect cellular energy expenditure towards biomass accumulation. While oxidative phosphorylation efficiently generates ATP, allowing for high protein translation, it does not provide the substrates needed for lipogenesis. eEF2K, eukaryotic elongation factor 2 kinase.

Figure 2

AMPK is a regulatory node in energy metabolism. Proliferating cells use Hk2-dependent aerobic glycolysis when glucose is not scarce, enabling the use of glucose intermediaries for biosynthesis. Hk2 deletion induced AMPK activation in medulloblastoma, suggesting that Hk2 functions in tumors to maintain AMPK in an inactive state. During energy stress, increasing AMP:ATP ratio induces the phosphorylation and activation of AMPK. In turn, activated AMPK phosphorylates eEF2K and ACC1, to decrease protein translation and lipogenesis, respectively, while increasing fatty acid oxidation. AMPK thus maintains energy homeostasis in part by balancing lipogenesis and protein translation. Blocking both lipogenesis and the inhibition of translation may disrupt this homeostatic effect and improve the effectiveness of metabolic therapy. ACC1, acetyl-CoA carboxylase 1; AMP, adenosine monophosphate; AMPK, adenosine monophosphate-activated protein kinase; eEF2, eukaryotic elongation factor 2; eEF2K, eukaryotic elongation factor 2 kinase; Hk2, hexokinase 2.