The anti-angiogenic action of 2-deoxyglucose involves attenuation of VEGFR2 signaling and MMP-2 expression in HUVECs.
OBJECTIVE
2-Deoxyglucose (2-DG) is a glucose analogue and has been shown to inhibit angiogenesis in human umbilical vascular endothelial cells (HUVECs) through interference with N-linked glycosylation. However, the anti-angiogenic mechanisms of 2-DG are not fully elucidated.


METHODS
We first employed an ex vivo rat aortic ring model to substantiate the anti-angiogenic action of 2-DG and then used HUVECs to investigate the molecular mechanism underlying such an action.


RESULTS
Results reveal that 2-DG (0.05-1.0mM) significantly inhibited tube formation in both rat aortic rings and HUVECs. 2-DG (0.1-1.0mM) also significantly inhibited cell invasion and migration, as well as the activity and mRNA and protein expression of matrix metalloproteinase (MMP)-2 in HUVECs. In addition, 2-DG (1.0mM) significantly inhibited mRNA and protein expression of vascular endothelial growth receptor 2 (VEGFR2) in a time-dependent manner. 2-DG also significantly inhibited the phosphorylation of the focal adhesion kinase (FAK) and mitogen-activated protein kinase (p38), the downstream molecules of VEGFR2. The effects of 2-DG on tube formation, MMP-2 activity, and VEGFR2 protein expression in HUVECs were reversed by mannose, an N-linked glycosylation precursor. Mannose also reversed 2-DG-induced accumulation of VEGFR2 in the endoplasmic reticulum.


CONCLUSIONS
This ex vivo and in vitro study demonstrates that 2-DG inhibits angiogenesis with an action involving attenuation of VEGFR2 signaling and MMP-2 expression, possibly resulting from interference with N-linked glycosylation of VEGFR2. Further studies are needed to show that 2-DG inhibits VEGF-mediated angiogenesis or that the actual status of N-glycosylation of VEGFR2 is affected by the treatment.
Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan.
I-Chen
IC
Chuang
Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan.
Chih-Min
CM
Yang
Department of BioIndustry Technology, Dayeh University, Changhua, Taiwan.
Tuzz-Ying
TY
Song
School of Nutrition, Chung Shan Medical University, Taichung, Taiwan; Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: naeman@csmu.edu.tw.
Nae-Cherng
NC
Yang
Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan; Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan. Electronic address: mlhuhu@nchu.edu.tw.
Miao-Lin
ML
Hu
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008297:Male; D008358:Mannose / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D003847:Deoxyglucose; D040301:Vascular Endothelial Growth Factor Receptor-2; D020778:Matrix Metalloproteinase 2; D008358:Mannose
2-Deoxyglucose; Angiogenesis; Human umbilical vascular endothelial cells; Mannose; Vascular endothelial growth factor receptor-2