Protein N-glycosylation alteration and glycolysis inhibition both contribute to the antiproliferative action of 2-deoxyglucose in breast cancer cells
Protein N-glycosylation alteration and glycolysis inhibition both contribute to the antiproliferative action of 2-deoxyglucose in breast cancer cells
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DOI：
10.1007/s10549-018-4874-z
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发表时间：
2018-10-01
影响因子：
3.8
通讯作者：
Flament, Stephane
中科院分区：
文献类型：
--
作者：
Berthe, Audrey;Zaffino, Marie;Flament, Stephane
癌细胞通常比正常细胞引起更高的糖酵解速率，支持糖酵解抑制剂作为治疗剂的发展。2-脱氧葡萄糖（2-DG）由于其与葡萄糖竞争的能力而用于此背景下。然而，许多研究没有考虑到2-DG不仅抑制糖酵解，而且抑制N-糖基化。由于有有限的出版物2-DG在乳腺癌中的作用机制，我们研究了其在乳腺癌细胞系中的作用，以确定所发挥的糖酵解抑制和N-连接的糖基化interference.Methods和Results 2-脱氧葡萄糖表现为一种抗癌剂，具有类似的效率对细胞数量减少之间的乳腺癌依赖MCF-7和乳腺癌独立的MDA-MB-231乳腺癌细胞。它也干扰了N-连接的糖基化过程中的两个细胞系所示的溶酶体相关膜蛋白2和钙调蛋白的迁移曲线。这些结果得到加强的外观上的脂质连接的寡糖和N-连接的糖蛋白的2-DG孵育的MDA-MB-231细胞的异常Man 7 GlcNAc 2结构。此外，2-DG诱导的瞬时内质网应激在MDA-MB-231细胞中更持久。这两种变化都被甘露糖消除。2-DG，即使在甘露糖的存在下，在两个细胞系中的糖酵解减少。甘露糖可部分逆转2-DG对细胞数的影响，其中N-糖基化干扰作用在MDA-MB-231和MCF-7细胞中分别占2-DG抗肿瘤作用的37%和47%。
PurposeCancer cells often elicit a higher glycolytic rate than normal cells, supporting the development of glycolysis inhibitors as therapeutic agents. 2-Deoxyglucose (2-DG) is used in this context due to its ability to compete with glucose. However, many studies do not take into account that 2-DG inhibits not only glycolysis but also N-glycosylation. Since there are limited publications on 2-DG mechanism of action in breast cancer, we studied its effects in breast cancer cell lines to determine the part played by glycolysis inhibition and N-linked glycosylation interference.Methods and Results2-Deoxyglucose behaved as an anticancer agent with a similar efficiency on cell number decrease between the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cells. It also interfered with the N-linked glycosylation process in both cell lines as illustrated by the migration profile of the lysosomal-associated membrane protein 2 and calumenin. These results are reinforced by the appearance of an abnormal Man7GlcNAc2 structure both on lipid-linked oligosaccharides and N-linked glycoproteins of 2-DG incubated MDA-MB-231 cells. Besides, 2-DG-induced a transient endoplasmic reticulum stress that was more sustained in MDA-MB-231 cells. Both changes were abrogated by mannose. 2-DG, even in the presence of mannose, decreased glycolysis in both cell lines. Mannose partially reversed the effects of 2-DG on cell numbers with N-linked glycosylation interference accounting for 37 and 47% of 2-DG anti-cancerous effects in MDA-MB-231 and MCF-7 cells, respectively.ConclusionN-linked glycosylation interference and glycolysis disruption both contribute to the anticancer properties of 2-DG in breast cancer cells.