SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance.
SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance.
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DOI：
10.1038/nature14363
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发表时间：
2015-04-16
期刊：
影响因子：
64.8
通讯作者：
Sabatini DM
中科院分区：
文献类型：
--
作者：
Kim D;Fiske BP;Birsoy K;Freinkman E;Kami K;Possemato RL;Chudnovsky Y;Pacold ME;Chen WW;Cantor JR;Shelton LM;Gui DY;Kwon M;Ramkissoon SH;Ligon KL;Kang SW;Snuderl M;Vander Heiden MG;Sabatini DM
癌细胞调整其代谢过程以支持快速增殖，但人们对癌细胞如何改变代谢以促进细胞在血管化不良的肿瘤微环境中的生存知之甚少。在这里，我们确定了丝氨酸和甘氨酸代谢在神经胶质瘤缺血区内脑癌细胞存活中的关键作用。在人多形性胶质母细胞瘤 (GBM) 中，线粒体丝氨酸羟甲基转移酶 (SHMT2) 和甘氨酸脱羧酶 (GLDC) 在坏死灶周围的假栅栏细胞中高度表达。我们发现 SHMT2 活性限制丙酮酸激酶 (PKM2) 的活性并减少耗氧量，从而引发代谢状态，从而为血管化不良的肿瘤区域的细胞赋予深远的生存优势。 GLDC 抑制会损害 SHMT2 水平高的细胞，因为 GLDC 未代谢的过量甘氨酸可转化为有毒分子氨基丙酮和甲基乙二醛。因此，SHMT2是癌细胞适应肿瘤环境所必需的，但也使这些细胞对甘氨酸裂解系统抑制敏感。
Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumor microenvironment. Here, we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischemic zones of gliomas. In human glioblastoma multiforme (GBM), mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumor regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumor environment, but also renders these cells sensitive to glycine cleavage system inhibition.