Abstract
Increased glucose utilization is a feature of cancer cells to support cell survival, proliferation, and metastasis. An association between diabetes mellitus and cancer progression was previously demonstrated in cancers including cholangiocarcinoma (CCA). This study was aimed to determine the effects of high glucose on protein O-GlcNAcylation and metastatic potentials of CCA cells. Two pairs each of the parental low metastatic and highly metastatic CCA sublines were cultured in normal (5.6 mM) or high (25 mM) glucose media. The migration and invasion abilities were determined and underlying mechanisms were explored. Results revealed that high glucose promoted migration and invasion of CCA cells that were more pronounced in the highly metastatic sublines. Concomitantly, high glucose increased global O-GlcNAcylated proteins, the expressions of vimentin, hexokinase, glucosamine-fructose-6-phosphate amidotransferase (GFAT) and O-GlcNAc transferase of CCA cells. The glucose level that promoted migration/invasion was shown to be potentiated by the induction of GFAT, O-GlcNAcylation and an increase of O-GlcNAcylated vimentin and vimentin expression. Treatment with a GFAT inhibitor reduced global O-GlcNAcylated proteins, vimentin expression, and alleviated cell migration. Altogether, these results suggested the role of high glucose enhanced CCA metastasis via modulation of O-GlcNAcylation, through the expressions of GFAT and vimentin.
Highlights
(UDP-GlcNAc), a substrate for glycosylation, e.g., O-GlcNAcylation
The present study shows for the first time in the results, the implications of high glucose on HBP-modulated O-GlcNAcylation and aggressiveness of CCA cells
Several studies reported the significance of glucose in promoting epithelial-mesenchymal transition (EMT) and metastasis of cancer
Summary
The rate of HBP can be regulated by the concentrations of the substrates, such as glucose and GlcNAc, or controlled by an expression of the rate limiting enzyme; glucosamine-fructose-6-phosphate amidotransfrase (GFAT)[14,15]. Increasing glucose uptake may promote glucose flux through HBP and subsequently increase O-GlcNAcylation. The present study was designed to test the crucial role of high glucose in promoting CCA cell migration/invasion, which, was found to be more pronounced in the highly metastatic cells. The tests in this study were further designed to indicate if the association between high glucose and HBP activation in CCA cells does occur, which would subsequently increase O-GlcNAcylation and expression of vimentin, leading to the increased motility of cells. The present study shows for the first time in the results, the implications of high glucose on HBP-modulated O-GlcNAcylation and aggressiveness of CCA cells. The findings from this study, fulfill the understanding of hyperglycemic conditions promoting CCA progression, and suggest the possible use of GFAT as a new therapeutic target for CCA treatment
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