O-GlcNAc Protein Modification in Cancer Cells Increases in Response to Glucose Deprivation through Glycogen Degradation
O-GlcNAc Protein Modification in Cancer Cells Increases in Response to Glucose Deprivation through Glycogen Degradation
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DOI：
10.1074/jbc.m109.026351
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发表时间：
2009-12-11
影响因子：
4.8
通讯作者：
Cho, Jin Won
中科院分区：
文献类型：
--
作者：
Kang, Jeong Gu;Park, Sang Yoon;Cho, Jin Won
当细胞葡萄糖浓度低于正常水平时，通常蛋白质O-GlcNAc修饰（O-GlcNAc化）的程度降低。然而，最近的报道表明，在HepG 2和Neuro-2a细胞中，通过葡萄糖剥夺增加O-GlcNAc化。在这里，我们报告了非小细胞肺癌A549细胞和各种其他细胞在葡萄糖剥夺反应中O-GlcNAc化的增加。虽然O-GlcNAc转移酶的水平不变，但该酶含有较少的O-GlcNAc，并且其活性增加。此外，O-GlcNAcase活性降低。所研究的细胞中含有糖原，我们表明，它的降解葡萄糖剥夺提供了一个来源的UDP-GlcNAc所需的增加O-GlcNAc酰化在这种条件下。这需要活性糖原磷酸化酶，并导致增加谷氨酰胺：果糖-6-磷酸酰胺转移酶，第一和限速酶在己糖胺生物合成途径。有趣的是，葡萄糖剥夺减少了磷酸果糖激酶1（一种调节性糖酵解酶）的量，并阻断了ATP的合成。这些发现表明，糖原是增加O-GlcNAc化的来源，但不是响应于葡萄糖剥夺而产生ATP的来源，这可能有助于癌细胞存活。
When cellular glucose concentrations fall below normal levels, in general the extent of protein O-GlcNAc modification (O-GlcNAcylation) decreases. However, recent reports demonstrated increased O-GlcNAcylation by glucose deprivation in HepG2 and Neuro-2a cells. Here, we report increased O-GlcNAcylation in non-small cell lung carcinoma A549 cells and various other cells in response to glucose deprivation. Although the level of O-GlcNAc transferase was unchanged, the enzyme contained less O-GlcNAc, and its activity was increased. Moreover, O-GlcNAcase activity was reduced. The studied cells contain glycogen, and we show that its degradation in response to glucose deprivation provides a source for UDP-GlcNAc required for increased O-GlcNAcylation under this condition. This required active glycogen phosphorylase and resulted in increased glutamine: fructose-6-phosphate amidotransferase, the first and rate-limiting enzyme in the hexosamine biosynthetic pathway. Interestingly, glucose deprivation reduced the amount of phosphofructokinase 1, a regulatory glycolytic enzyme, and blocked ATP synthesis. These findings suggest that glycogen is the source for increased O-GlcNAcylation but not for generating ATP in response to glucose deprivation and that this may be useful for cancer cells to survive.