Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation
Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation
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DOI：
10.1158/1535-7163.mct-07-0310
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发表时间：
2007-11-01
影响因子：
5.7
通讯作者：
Lampidis, Theodore J.
中科院分区：
文献类型：
--
作者：
Kurtoglu, Metin;Gao, Ningguo;Lampidis, Theodore J.
在缺氧条件下生长的肿瘤细胞中，用2-脱氧-D-葡萄糖（2-DG）抑制糖酵解导致细胞死亡，而在常氧条件下，类似处理的细胞存活。令人惊讶的是，在这里，我们发现2-DG是有毒的选择肿瘤细胞系生长在正常的氧张力。相比之下，一个更有效的糖酵解抑制剂，2-氟脱氧-D-葡萄糖，在这些细胞类型中显示很少或没有毒性，表明糖酵解抑制以外的机制是负责他们的敏感性，2-DG在常氧。另一种机制的线索来自以前的研究，其中显示2-DG干扰病毒N-连接的糖基化，并且通过外源性添加甘露糖是可逆的。同样，我们发现，2-DG干扰N-连接的糖基化更有力地在肿瘤细胞类型是敏感的2-DG在常氧下，这可以逆转外源性甘露糖。此外，2-DG诱导未折叠蛋白质应答，包括GADD 153（C/EBP同源蛋白）的上调，GADD 153是细胞凋亡的未折叠蛋白质应答特异性介质，在2-DG敏感细胞中更有效。我们的结论是，2-DG似乎是，在选择肿瘤细胞类型生长在常氧抑制N-连接的糖基化，而不是糖酵解毒性。因为在I期研究中，2-DG与抗癌剂组合使用以靶向低氧细胞，所以我们的结果提高了以下可能性：在某些情况下，2-DG可用作单一药剂以选择性地杀死实体瘤的需氧（通过干扰糖基化）和低氧（通过抑制糖酵解）细胞。[Mol Cancer Ther 2007;6（11）：3049-58]。
In tumor cells growing under hypoxia, inhibiting glycolysis with 2-deoxy-D-glucose (2-DG) leads to cell death whereas under normoxic conditions cells similarly treated survive. Surprisingly, here we find that 2-DG is toxic in select tumor cell lines growing under normal oxygen tension. In contrast, a more potent glycolytic inhibitor, 2-fluorodeoxy-D-glucose, shows little or no toxicity in these cell types, indicating that a mechanism other than inhibition of glycolysis is responsible for their sensitivity to 2-DG under normoxia. A clue to this other mechanism comes from previous studies in which it was shown that 2-DG interferes with viral N-linked glycosylation and is reversible by exogenous addition of mannose. Similarly, we find that 2-DG interferes with N-linked glycosylation more potently in the tumor cell types that are sensitive to 2-DG under normoxia, which can be reversed by exogenous mannose. Additionally, 2-DG induces an unfolded protein response, including up-regulation of GADD153 (C/ EBP-homologous protein), an unfolded protein response-specific mediator of apoptosis, more effectively in 2-DG - sensitive cells. We conclude that 2-DG seems to be, toxic in select tumor cell types growing under normoxia by inhibition of N-linked glycosylation and not by glycolysis. Because in a phase I study 2-DG is used in combination with an anticancer agent to target hypoxic cells, our results raise the possibility that in certain cases, 2-DG could be used as a single agent to selectively kill both the aerobic (via interference with glycosylation) and hypoxic (via inhibition of glycolysis) cells of a solid tumor. [Mol Cancer Ther 2007;6(11):3049-58].