Cargando…

An Integrated Proteomic and Glycoproteomic Investigation Reveals Alterations in the N-Glycoproteomic Network Induced by 2-Deoxy-D-Glucose in Colorectal Cancer Cells

As a well-known glycolysis inhibitor for anticancer treatment, 2-Deoxy-D-glucose (2DG) inhibits the growth and survival of cancer cells by interfering with the ATP produced by the metabolism of D-glucose. In addition, 2DG inhibits protein glycosylation in vivo by competing with D-mannose, leading to...

Descripción completa

Detalles Bibliográficos
Autores principales: Ma, Cheng, Tsai, Hong-Yuan, Zhang, Qi, Senavirathna, Lakmini, Li, Lian, Chin, Lih-Shen, Chen, Ru, Pan, Sheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331968/
https://www.ncbi.nlm.nih.gov/pubmed/35897829
http://dx.doi.org/10.3390/ijms23158251
_version_ 1784758533048238080
author Ma, Cheng
Tsai, Hong-Yuan
Zhang, Qi
Senavirathna, Lakmini
Li, Lian
Chin, Lih-Shen
Chen, Ru
Pan, Sheng
author_facet Ma, Cheng
Tsai, Hong-Yuan
Zhang, Qi
Senavirathna, Lakmini
Li, Lian
Chin, Lih-Shen
Chen, Ru
Pan, Sheng
author_sort Ma, Cheng
collection PubMed
description As a well-known glycolysis inhibitor for anticancer treatment, 2-Deoxy-D-glucose (2DG) inhibits the growth and survival of cancer cells by interfering with the ATP produced by the metabolism of D-glucose. In addition, 2DG inhibits protein glycosylation in vivo by competing with D-mannose, leading to endoplasmic reticulum (ER) stress and unfolded protein responses in cancer cells. However, the molecular details underlying the impact of 2DG on protein glycosylation remain largely elusive. With an integrated approach to glycoproteomics and proteomics, we characterized the 2DG-induced alterations in N-glycosylation, as well as the cascading impacts on the whole proteome using the HT29 colorectal cancer cell line as a model system. More than 1700 site-specific glycoforms, represented by unique intact glycopeptides (IGPs), were identified. The treatment of 2DG had a broad effect on the N-glycoproteome, especially the high-mannose types. The glycosite occupancy of the high-mannose N-glycans decreased the most compared with the sialic acid and fucose-containing N-glycans. Many of the proteins with down-regulated high-mannose were implicated in functional networks related to response to topologically incorrect protein, integrin-mediated signaling, lysosomal transport, protein hydroxylation, vacuole, and protein N-glycosylation. The treatment of 2DG also functionally disrupted the global cellular proteome, evidenced by significant up-regulation of the proteins implicated in protein folding, endoplasmic reticulum, mitochondrial function, cellular respiration, oxidative phosphorylation, and translational termination. Taken together, these findings reveal the complex changes in protein glycosylation and expression underlying the various effects of 2DG on cancer cells, and may provide insightful clues to inform therapeutic development targeting protein glycosylation.
format Online
Article
Text
id pubmed-9331968
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-93319682022-07-29 An Integrated Proteomic and Glycoproteomic Investigation Reveals Alterations in the N-Glycoproteomic Network Induced by 2-Deoxy-D-Glucose in Colorectal Cancer Cells Ma, Cheng Tsai, Hong-Yuan Zhang, Qi Senavirathna, Lakmini Li, Lian Chin, Lih-Shen Chen, Ru Pan, Sheng Int J Mol Sci Article As a well-known glycolysis inhibitor for anticancer treatment, 2-Deoxy-D-glucose (2DG) inhibits the growth and survival of cancer cells by interfering with the ATP produced by the metabolism of D-glucose. In addition, 2DG inhibits protein glycosylation in vivo by competing with D-mannose, leading to endoplasmic reticulum (ER) stress and unfolded protein responses in cancer cells. However, the molecular details underlying the impact of 2DG on protein glycosylation remain largely elusive. With an integrated approach to glycoproteomics and proteomics, we characterized the 2DG-induced alterations in N-glycosylation, as well as the cascading impacts on the whole proteome using the HT29 colorectal cancer cell line as a model system. More than 1700 site-specific glycoforms, represented by unique intact glycopeptides (IGPs), were identified. The treatment of 2DG had a broad effect on the N-glycoproteome, especially the high-mannose types. The glycosite occupancy of the high-mannose N-glycans decreased the most compared with the sialic acid and fucose-containing N-glycans. Many of the proteins with down-regulated high-mannose were implicated in functional networks related to response to topologically incorrect protein, integrin-mediated signaling, lysosomal transport, protein hydroxylation, vacuole, and protein N-glycosylation. The treatment of 2DG also functionally disrupted the global cellular proteome, evidenced by significant up-regulation of the proteins implicated in protein folding, endoplasmic reticulum, mitochondrial function, cellular respiration, oxidative phosphorylation, and translational termination. Taken together, these findings reveal the complex changes in protein glycosylation and expression underlying the various effects of 2DG on cancer cells, and may provide insightful clues to inform therapeutic development targeting protein glycosylation. MDPI 2022-07-26 /pmc/articles/PMC9331968/ /pubmed/35897829 http://dx.doi.org/10.3390/ijms23158251 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ma, Cheng
Tsai, Hong-Yuan
Zhang, Qi
Senavirathna, Lakmini
Li, Lian
Chin, Lih-Shen
Chen, Ru
Pan, Sheng
An Integrated Proteomic and Glycoproteomic Investigation Reveals Alterations in the N-Glycoproteomic Network Induced by 2-Deoxy-D-Glucose in Colorectal Cancer Cells
title An Integrated Proteomic and Glycoproteomic Investigation Reveals Alterations in the N-Glycoproteomic Network Induced by 2-Deoxy-D-Glucose in Colorectal Cancer Cells
title_full An Integrated Proteomic and Glycoproteomic Investigation Reveals Alterations in the N-Glycoproteomic Network Induced by 2-Deoxy-D-Glucose in Colorectal Cancer Cells
title_fullStr An Integrated Proteomic and Glycoproteomic Investigation Reveals Alterations in the N-Glycoproteomic Network Induced by 2-Deoxy-D-Glucose in Colorectal Cancer Cells
title_full_unstemmed An Integrated Proteomic and Glycoproteomic Investigation Reveals Alterations in the N-Glycoproteomic Network Induced by 2-Deoxy-D-Glucose in Colorectal Cancer Cells
title_short An Integrated Proteomic and Glycoproteomic Investigation Reveals Alterations in the N-Glycoproteomic Network Induced by 2-Deoxy-D-Glucose in Colorectal Cancer Cells
title_sort integrated proteomic and glycoproteomic investigation reveals alterations in the n-glycoproteomic network induced by 2-deoxy-d-glucose in colorectal cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331968/
https://www.ncbi.nlm.nih.gov/pubmed/35897829
http://dx.doi.org/10.3390/ijms23158251
work_keys_str_mv AT macheng anintegratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT tsaihongyuan anintegratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT zhangqi anintegratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT senavirathnalakmini anintegratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT lilian anintegratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT chinlihshen anintegratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT chenru anintegratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT pansheng anintegratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT macheng integratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT tsaihongyuan integratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT zhangqi integratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT senavirathnalakmini integratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT lilian integratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT chinlihshen integratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT chenru integratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells
AT pansheng integratedproteomicandglycoproteomicinvestigationrevealsalterationsinthenglycoproteomicnetworkinducedby2deoxydglucoseincolorectalcancercells