Antiangiogenic activity of 2-deoxy-D-glucose.
<h4>Background</h4>During tumor angiogenesis, endothelial cells (ECs) are engaged in a number of energy consuming biological processes, such as proliferation, migration, and capillary formation. Since glucose uptake and metabolism are increased to meet this energy need, the effects of th...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-10-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0013699&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850236471666016256 |
|---|---|
| author | Jaime R Merchan Krisztina Kovács Jaclyn W Railsback Metin Kurtoglu Yuqi Jing Yolanda Piña Ningguo Gao Timothy G Murray Mark A Lehrman Theodore J Lampidis |
| author_facet | Jaime R Merchan Krisztina Kovács Jaclyn W Railsback Metin Kurtoglu Yuqi Jing Yolanda Piña Ningguo Gao Timothy G Murray Mark A Lehrman Theodore J Lampidis |
| author_sort | Jaime R Merchan |
| collection | DOAJ |
| description | <h4>Background</h4>During tumor angiogenesis, endothelial cells (ECs) are engaged in a number of energy consuming biological processes, such as proliferation, migration, and capillary formation. Since glucose uptake and metabolism are increased to meet this energy need, the effects of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) on in vitro and in vivo angiogenesis were investigated.<h4>Methodology/principal findings</h4>In cell culture, 2-DG inhibited EC growth, induced cytotoxicity, blocked migration, and inhibited actively forming but not established endothelial capillaries. Surprisingly, 2-DG was a better inhibitor of these EC properties than two more efficacious glycolytic inhibitors, 2-fluorodeoxy-D-glucose and oxamate. As an alternative to a glycolytic inhibitory mechanism, we considered 2-DG's ability to interfere with endothelial N-linked glycosylation. 2-DG's effects were reversed by mannose, an N-linked glycosylation precursor, and at relevant concentrations 2-DG also inhibited synthesis of the lipid linked oligosaccharide (LLO) N-glycosylation donor in a mannose-reversible manner. Inhibition of LLO synthesis activated the unfolded protein response (UPR), which resulted in induction of GADD153/CHOP and EC apoptosis (TUNEL assay). Thus, 2-DG's effects on ECs appeared primarily due to inhibition of LLOs synthesis, not glycolysis. 2-DG was then evaluated in two mouse models, inhibiting angiogenesis in both the matrigel plug assay and the LH(BETA)T(AG) transgenic retinoblastoma model.<h4>Conclusions/significance</h4>In conclusion, 2-DG inhibits endothelial cell angiogenesis in vitro and in vivo, at concentrations below those affecting tumor cells directly, most likely by interfering with N-linked glycosylation rather than glycolysis. Our data underscore the importance of glucose metabolism on neovascularization, and demonstrate a novel approach for anti-angiogenic strategies. |
| format | Article |
| id | doaj-art-1a87ae1e5f1b4f9ea8df589895b9e1e0 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2010-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-1a87ae1e5f1b4f9ea8df589895b9e1e02025-08-20T02:01:57ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-10-01510e1369910.1371/journal.pone.0013699Antiangiogenic activity of 2-deoxy-D-glucose.Jaime R MerchanKrisztina KovácsJaclyn W RailsbackMetin KurtogluYuqi JingYolanda PiñaNingguo GaoTimothy G MurrayMark A LehrmanTheodore J Lampidis<h4>Background</h4>During tumor angiogenesis, endothelial cells (ECs) are engaged in a number of energy consuming biological processes, such as proliferation, migration, and capillary formation. Since glucose uptake and metabolism are increased to meet this energy need, the effects of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) on in vitro and in vivo angiogenesis were investigated.<h4>Methodology/principal findings</h4>In cell culture, 2-DG inhibited EC growth, induced cytotoxicity, blocked migration, and inhibited actively forming but not established endothelial capillaries. Surprisingly, 2-DG was a better inhibitor of these EC properties than two more efficacious glycolytic inhibitors, 2-fluorodeoxy-D-glucose and oxamate. As an alternative to a glycolytic inhibitory mechanism, we considered 2-DG's ability to interfere with endothelial N-linked glycosylation. 2-DG's effects were reversed by mannose, an N-linked glycosylation precursor, and at relevant concentrations 2-DG also inhibited synthesis of the lipid linked oligosaccharide (LLO) N-glycosylation donor in a mannose-reversible manner. Inhibition of LLO synthesis activated the unfolded protein response (UPR), which resulted in induction of GADD153/CHOP and EC apoptosis (TUNEL assay). Thus, 2-DG's effects on ECs appeared primarily due to inhibition of LLOs synthesis, not glycolysis. 2-DG was then evaluated in two mouse models, inhibiting angiogenesis in both the matrigel plug assay and the LH(BETA)T(AG) transgenic retinoblastoma model.<h4>Conclusions/significance</h4>In conclusion, 2-DG inhibits endothelial cell angiogenesis in vitro and in vivo, at concentrations below those affecting tumor cells directly, most likely by interfering with N-linked glycosylation rather than glycolysis. Our data underscore the importance of glucose metabolism on neovascularization, and demonstrate a novel approach for anti-angiogenic strategies.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0013699&type=printable |
| spellingShingle | Jaime R Merchan Krisztina Kovács Jaclyn W Railsback Metin Kurtoglu Yuqi Jing Yolanda Piña Ningguo Gao Timothy G Murray Mark A Lehrman Theodore J Lampidis Antiangiogenic activity of 2-deoxy-D-glucose. PLoS ONE |
| title | Antiangiogenic activity of 2-deoxy-D-glucose. |
| title_full | Antiangiogenic activity of 2-deoxy-D-glucose. |
| title_fullStr | Antiangiogenic activity of 2-deoxy-D-glucose. |
| title_full_unstemmed | Antiangiogenic activity of 2-deoxy-D-glucose. |
| title_short | Antiangiogenic activity of 2-deoxy-D-glucose. |
| title_sort | antiangiogenic activity of 2 deoxy d glucose |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0013699&type=printable |
| work_keys_str_mv | AT jaimermerchan antiangiogenicactivityof2deoxydglucose AT krisztinakovacs antiangiogenicactivityof2deoxydglucose AT jaclynwrailsback antiangiogenicactivityof2deoxydglucose AT metinkurtoglu antiangiogenicactivityof2deoxydglucose AT yuqijing antiangiogenicactivityof2deoxydglucose AT yolandapina antiangiogenicactivityof2deoxydglucose AT ningguogao antiangiogenicactivityof2deoxydglucose AT timothygmurray antiangiogenicactivityof2deoxydglucose AT markalehrman antiangiogenicactivityof2deoxydglucose AT theodorejlampidis antiangiogenicactivityof2deoxydglucose |