Abstract
Alterations in glucose and glutamine utilizing pathways and in fatty acid metabolism are currently considered the most significant and prevalent metabolic changes observed in almost all types of tumors. Glucose, glutamine and fatty acids are the substrates for the hexosamine biosynthetic pathway (HBP). This metabolic pathway generates the “sensing molecule” UDP-N-Acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is the substrate for the enzymes involved in protein N- and O-glycosylation, two important post-translational modifications (PTMs) identified in several proteins localized in the extracellular space, on the cell membrane and in the cytoplasm, nucleus and mitochondria. Since protein glycosylation controls several key aspects of cell physiology, aberrant protein glycosylation has been associated with different human diseases, including cancer. Here we review recent evidence indicating the tight association between the HBP flux and cell metabolism, with particular emphasis on the post-transcriptional and transcriptional mechanisms regulated by the HBP that may cause the metabolic rewiring observed in cancer. We describe the implications of both protein O- and N-glycosylation in cancer cell metabolism and bioenergetics; focusing our attention on the effect of these PTMs on nutrient transport and on the transcriptional regulation and function of cancer-specific metabolic pathways.
Highlights
Cancer cell growth is tightly correlated to an altered cellular metabolism
Among the different metabolic pathways identified in cancer, an important role has been assigned to the hexosamine biosynthetic pathway (HBP)
UDP-GlcNAc, able to lead to a fine adjustment of the cellular metabolism in direct correlation with nutrient variations
Summary
Cancer cell growth is tightly correlated to an altered cellular metabolism. In particular, as Warburg noticed almost one century ago, cancer cells, even in the presence of oxygen, produce Adenosine. UDP-GlcNAc is the substrate for a less complex type of glycoconjugate, the protein O-GlcNAcylation [7], which has been found on many cytoplasmic, nuclear and mitochondrial proteins, and is considered a dynamic PTM, analogous to phosphorylation, regulating many cellular functions [8]. This metabolite is not directly involved in any anabolic process, since it fundamentally serves, as previously described, as a building block for protein- and lipid-glycoconjugate biosynthesis [5,6,7,10] In this context, the ability of HBP to integrate and sense the main intracellular metabolites strongly supports the important role of this pathway and of its final product UDP-GlcNAc in the regulation of cell metabolism both in physiological conditions and in the metabolic changes observed in several human diseases, such as cancer. In this review we explore the connection between the HBP and cell metabolism with a particular emphasis on the association between HBP and the metabolic rewiring observed in cancer cells
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