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首页> 外文期刊>Cell cycle >Druggable glycolytic requirement for Hedgehog-dependent neuronal and medulloblastoma growth
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Druggable glycolytic requirement for Hedgehog-dependent neuronal and medulloblastoma growth

机译：刺猬依赖的神经元和髓母细胞瘤生长的可药用糖酵解要求

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Aberrant activation of SHH pathway is a major cause of medulloblastoma (MB), the most frequent brain malignancy of the childhood. A few Hedgehog inhibitors, all antagonizing the membrane transducer Smo, have been approved or are under clinical trials for the treatment of human MB. However, the efficacy of these drugs is limited by the occurrence of novel mutations or by activation of downstream or non-canonical Hedgehog components. Thus, the identification of novel druggable downstream pathways represents a critical step to overcome this problem. In the present work we demonstrate that aerobic glycolysis is a valuable HH-dependent downstream target, since its inhibition significantly counteracts the HH-mediated growth of normal and tumor cells. Hedgehog activation induces transcription of hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2), two key gatekeepers of glycolysis. The process is mediated by the canonical activation of the Gli transcription factors and causes a robust increase of extracellular lactate concentration. We show that inhibition of glycolysis at different levels blocks the Hedgehog-induced proliferation of granule cell progenitors (GCPs), the cells from which medulloblastoma arises. Remarkably, we demonstrate that this glycolytic transcriptional program is also upregulated in SHH-dependent tumors and that pharmacological targeting with the pyruvate kinase inhibitor dichloroacetate (DCA) efficiently represses MB growth in vitro and in vivo. Together, these data illustrate a previously uncharacterized pharmacological strategy to target Hedgehog dependent growth, which can be exploited for the treatment of medulloblastoma patients.
机译：SHH途径的异常激活是髓母细胞瘤（MB）的主要原因，髓母细胞瘤是儿童时期最常见的脑恶性肿瘤。几种拮抗膜换能器Smo的刺猬抑制剂已被批准或正处于治疗人MB的临床试验中。但是，这些药物的功效受到新突变的出现或下游或非典型刺猬成分激活的限制。因此，新的药物下游通路的鉴定是克服这一问题的关键步骤。在目前的工作中，我们证明有氧糖酵解是有价值的HH依赖性下游靶标，因为它的抑制作用显着抵消了HH介导的正常细胞和肿瘤细胞的生长。刺猬激活诱导己糖激酶2（HK2）和丙酮酸激酶M2（PKM2）的转录，这是糖酵解的两个关键关守。该过程由Gli转录因子的规范激活介导，并引起细胞外乳酸浓度的强烈增加。我们表明抑制糖酵解在不同水平上阻止了刺猬诱导的颗粒细胞祖细胞（GCPs）的增殖，其中髓母细胞瘤是从这些细胞中产生的。值得注意的是，我们证明了这种糖酵解转录程序在SHH依赖的肿瘤中也被上调，并且用丙酮酸激酶抑制剂二氯乙酸盐（DCA）进行药理靶向在体外和体内均可有效抑制MB的生长。总之，这些数据说明了针对刺猬依赖性生长的以前未知的药理策略，可将其用于治疗髓母细胞瘤患者。

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