Hyperglycemia and aberrant O-GlcNAcylation: contributions to tumor progression

Abstract

A number of cancer types have shown an increased prevalence and a higher mortality rate in patients with hyperglycemic associated pathologies. Although the correlation between diabetes and cancer incidence has been increasingly reported, the underlying molecular mechanisms beyond this association are not yet fully understood. Recent studies have suggested that high glucose levels support tumor progression through multiple mechanisms that are hallmarks of cancer, including cell proliferation, resistance to apoptosis, increased cell migration and invasiveness, epigenetic regulation (hyperglycemic memory), resistance to chemotherapy and altered metabolism. Most of the above occur because hyperglycemia through hexosamine biosynthetic pathway leads to aberrant O-GlcNAcylation of many intracellular proteins that are involved in those mechanisms. Deregulated O-GlcNAcylation is emerging as a general feature of cancer. Despite strong evidence suggesting that aberrant O-GlcNAcylation is or may be involved in the acquisition of all cancer hallmarks, it remains out of the list of the next generation of emerging hallmarks. Here, we discuss some of the current understanding on how hyperglycemia affects cancer cell biology and how aberrant O-GlcNAcylation stands in this context.

Hexosamine Biosynthetic Pathway and Glycosylation Regulate Cell Migration in Melanoma Cells

“…However, transformed skin fibroblasts present increased expression of GFAT2, but no alterations in GFAT1 expression compared to normal skin tissue (45). Regarding HBP, most tumor types in which this pathway was analyzed present increased expression of HBP's rate-limiting enzyme, GFAT (6). However, in other tumors like gastric cancer the opposite happens, where a decrease in GFAT expression is found in tumors compared to normal tissue, and the expression of the enzyme is associated with a good prognosis of the disease (30).…”

“…The HBP is a branch of glycolysis responsible for the production of UDP- N -acetylglucosamine (UDP-GlcNAc). Its final product is considered an important nutrient sensor, since HBP uses as substrates molecules from carbohydrate (glucose), lipid (acetyl-CoA), amino acid (glutamine), and nucleotide (UTP) metabolism to generate UDP-GlcNAc (6). This metabolite is an activated monosaccharide used as substrate by glycosyltrasferases in glycosylation reactions of proteins and lipids, or to generate UDP-GlcNAc-derived activated monosaccharides, also used for glycosylation, such as UDP-GalNAc and CMP-Neu5Ac (7).…”

Hyperglycemia-Associated Dysregulation of O-GlcNAcylation and HIF1A Reduces Anticancer Action of Metformin in Ovarian Cancer Cells (SKOV-3)

“…Interestingly, we found that the proliferation of SKOV-3 cells cultured in hyperglycemia was significantly lower in comparison to normoglycemia. This is unusual for cancer cells because it is widely accepted that high glucose stimulates proliferation by satisfying energy and carbon needs [ 15 ]. Since O-GlcNAcylation is sensitive to metabolic state and is involved in tumor growth in vitro [ 16 ], we determined the expression of OGT and OGA mRNA.…”

Metabolic Labeling for the Visualization and Identification of Potentially O‐GlcNAc‐Modified Proteins

“…Even small shifts in global O‐GlcNAcylation levels have been implicated in a variety of diseases. O‐GlcNAc levels are consistently elevated in all types of cancer compared to healthy tissue (Ferrer, Sodi, & Reginato, 2016; Hanover, Chen, & Bond, 2018; Ma & Vosseller, 2013; Vasconcelos‐dos‐Santos, Queiroz, Rodrigues, Todeschini, & Dias, 2018) whereas the modification levels are lower in Alzheimer's disease (Aguilar, Hou, Wen, Wang, & Wu, 2017; Liu, Iqbal, Grundke‐Iqbal, Hart, & Gong, 2004; Liu et al., 2009; Pinho, Correia, Perry, Ambrósio, & Moreira, 2019). Taken together, these observations demonstrate the vital role of O‐GlcNAc in modulating biochemical pathways.…”