A catabolic block does not sufficiently explain how 2-deoxy-D-glucose inhibits cell growth
A catabolic block does not sufficiently explain how 2-deoxy-D-glucose inhibits cell growth
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DOI：
10.1073/pnas.0803090105
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发表时间：
2008-11-18
影响因子：
11.1
通讯作者：
Lehrach, Hans
中科院分区：
文献类型：
--
作者：
Ralser, Markus;Wamelink, Mirjarn M.;Lehrach, Hans
葡萄糖类似物2-脱氧-D-葡萄糖（2-DG）抑制正常和恶性细胞的生长，延长线虫的寿命，并且被广泛用作糖酵解抑制剂以研究与癌症、神经变性、热量限制和衰老有关的代谢活性。在这里，我们报告说，分离糖酵解和磷酸戊糖途径大大增加细胞耐受2-DG。这一发现表明，2-DG并不阻止细胞生长仅仅通过防止葡萄糖catalysis。此外，2-DG在野生型和2-DG抗性酵母菌株和人原代成纤维细胞中引起糖-磷酸中间体的类似浓度变化。最后，全基因组分析揭示了19个2-DG抗性酵母基因敲除，这些基因涉及碳水化合物代谢和线粒体稳态，以及核糖体生物合成、mRNA衰变、转录调控和细胞周期。因此，超出代谢块的过程是必不可少的2-DG的生物学特性。
The glucose analogue 2-deoxy-D-glucose (2-DG) restrains growth of normal and malignant cells, prolongs the lifespan of C elegans, and is widely used as a glycolytic inhibitor to study metabolic activity with regard to cancer, neurodegeneration, calorie restriction, and aging. Here, we report that separating glycolysis and the pentose phosphate pathway highly increases cellular tolerance to 2-DG. This finding indicates that 2-DG does not block cell growth solely by preventing glucose catabolism. In addition, 2-DG provoked similar concentration changes of sugar-phosphate intermediates in wild-type and 2-DG-resistant yeast strains and in human primary fibroblasts. Finally, a genome-wide analysis revealed 19 2-DG-resistant yeast knockouts of genes implicated in carbohydrate metabolism and mitochondrial homeostasis, as well as ribosome biogenesis, mRNA decay, transcriptional regulation, and cell cycle. Thus, processes beyond the metabolic block are essential for the biological properties of 2-DG.