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.
Transl Pediatr. 2015 Jan;4(1):12-9. doi: 10.3978/j.issn.2224-4336.2015.01.03.
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.
新的、毒性更小的疗法对于成神经管细胞瘤（儿童中最常见的恶性脑肿瘤）是必要的。与许多癌症一样，成神经管细胞瘤表现出明显不同于周围非肿瘤组织的代谢模式，并且高度组织化以支持肿瘤生长。成神经管细胞瘤代谢的关键方面，包括增加的脂肪生成和有氧糖酵解，源自神经祖细胞的代谢程序。在神经发育过程中，Sonic Hedgehog（Shh）信号诱导增殖祖细胞中的脂肪生成和有氧糖酵解，以支持快速生长。Shh 调节的转录诱导特定基因，包括己糖激酶 2（Hk2）和脂肪酸合酶（FASN），介导这些代谢模式。成神经管细胞瘤通过激活真核延伸因子 2 激酶（eEF2K）来限制蛋白质翻译，从而限制能量消耗，从而共同利用这些发育调节的代谢基因表达模式来维持肿瘤的持续生长。此外，成神经管细胞瘤通过激活真核延伸因子 2 激酶（eEF2K）限制蛋白质翻译，以限制能量消耗。eEF2K 的激活减少了生成 ATP 的需求，从而使对氧化磷酸化的依赖性降低，并通过有氧糖酵解增加葡萄糖的代谢。脂肪生成、有氧糖酵解和蛋白质翻译的限制在代谢过程的网络中运作，该网络通过单磷酸腺苷激活蛋白激酶（AMPK）进行整合以维持体内平衡。AMPK 的体内平衡效应有可能限制代谢靶向干预的影响。然而，通过联合靶向脂肪生成、糖酵解和 eEF2K，可以克服这种体内平衡效应。我们提出，联合靶向成神经管细胞瘤代谢可能产生有效抗癌治疗所需的协同作用。
