Department of Biology, Oral Cancer Research Institute, Korea.
J Biol Chem. 2009 Dec 11;284(50):34777-84. doi: 10.1074/jbc.M109.026351. Epub 2009 Oct 15.
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.
当细胞内葡萄糖浓度低于正常水平时，通常蛋白质的 O-GlcNAc 修饰（O-GlcNAcylation）程度会降低。然而，最近的报告表明，在 HepG2 和 Neuro-2a 细胞中，葡萄糖剥夺会导致 O-GlcNAcylation 增加。在这里，我们报告了非小细胞肺癌 A549 细胞以及其他各种细胞在葡萄糖剥夺时 O-GlcNAcylation 的增加。尽管 O-GlcNAc 转移酶的水平没有改变，但该酶中 O-GlcNAc 的含量减少，其活性增加。此外，O-GlcNAcase 的活性降低。研究中的细胞含有糖原，我们表明，糖原在葡萄糖剥夺时的降解为这种条件下增加的 O-GlcNAcylation 提供了所需的 UDP-GlcNAc 来源。这需要活跃的糖原磷酸化酶，并导致谷氨酰胺：果糖-6-磷酸酰胺转移酶增加，这是己糖生物合成途径中的第一个也是限速酶。有趣的是，葡萄糖剥夺会减少调节糖酵解的酶磷酸果糖激酶 1 的数量，并阻断 ATP 的合成。这些发现表明，糖原是增加 O-GlcNAcylation 的来源，但不是葡萄糖剥夺时生成 ATP 的来源，这对癌细胞的存活可能是有用的。
