Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma.
Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma.
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DOI：
10.1186/2049-3002-1-2
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发表时间：
2013-01-23
影响因子：
5.9
通讯作者：
Deshmukh M
中科院分区：
文献类型：
--
作者：
Gershon TR;Crowther AJ;Tikunov A;Garcia I;Annis R;Yuan H;Miller CR;Macdonald J;Olson J;Deshmukh M
虽然有氧糖酵解与癌症的不受约束的增殖有关，但对其生理作用知之甚少。因此，为什么这种促进肿瘤生长的代谢程序被保存在基因组中还没有得到解决。我们测试了有氧糖酵解来自调节快速增殖的发育过程的假设。我们进行了代谢和基因表达的综合分析，在小脑颗粒神经元祖细胞（CGNP）与和没有音速刺猬（Shh），他们的内源性有丝分裂原。因为我们的分析突出了己糖激酶-2（Hk 2）作为Shh诱导的关键代谢调节因子，我们研究了条件遗传Hk 2缺失在CGNP发育中的作用。然后，我们将Hk 2条件性基因敲除小鼠与发生自发性髓母细胞瘤的转基因SmoM 2小鼠杂交，并确定SmoM 2驱动的肿瘤发生的变化。我们发现Shh和磷酸肌醇3-激酶（PI 3 K）信号联合收割机诱导CGNP中Hk 2依赖性糖酵解表型。这种表型在成神经管细胞瘤（CGNP起源的恶性肿瘤）中重现。重要的是，cre介导的Hk 2消融消除了有氧糖酵解，破坏了CGNP的发育和Smoothened诱导的肿瘤发生。比较有髓母细胞瘤倾向的SmoM 2小鼠与无功能性Hk 2的肿瘤发生，我们证明有氧糖酵解的丧失降低了髓母细胞瘤的侵袭性，导致肿瘤生长为惰性病变，并允许荷瘤小鼠长期存活。我们的研究表明，癌症中的有氧糖酵解来自于持续存在于肿瘤发生中的发育机制。此外，我们在原发性肿瘤模型中证明了通过靶向Hk 2阻断有氧糖酵解的抗癌潜力。参见评论文章：http://www.biomedcentral.com/1741-7007/11/3
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. See commentary article:http://www.biomedcentral.com/1741-7007/11/3