Publication Date
7-26-2022
Journal
International Journal of Molecular Sciences
DOI
10.3390/ijms23158251
PMID
35897829
PMCID
PMC9331968
PubMedCentral® Posted Date
7-26-2022
PubMedCentral® Full Text Version
Post-Print
Published Open-Access
yes
Keywords
Colorectal Neoplasms, Deoxyglucose, Glucose, Glycosylation, Humans, Mannose, Proteome, Proteomics, 2-Deoxy-D-glucose, proteomics, glycoproteomics, mass spectrometry, colorectal cancer
Abstract
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.
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Digestive System Diseases Commons, Endocrine System Diseases Commons, Endocrinology, Diabetes, and Metabolism Commons, Gastroenterology Commons
Comments
Associated Data
Data Availability Statement