Abstract
UDP-glucose ceramide glucosyltransferase (UGCG) is the key enzyme in glycosphingolipid (GSL) metabolism by being the only enzyme that generates glucosylceramide (GlcCer) de novo. Increased UGCG synthesis is associated with pro-cancerous processes such as increased proliferation and multidrug resistance in several cancer types. We investigated the influence of UGCG overexpression on glutamine metabolism in breast cancer cells. We observed adapted glucose and glutamine uptake in a limited energy supply environment following UGCG overexpression. Glutamine is used for reinforced oxidative stress response shown by increased mRNA expression of glutamine metabolizing proteins such as glutathione-disulfide reductase (GSR) resulting in increased reduced glutathione (GSH) level. Augmented glutamine uptake is also used for fueling the tricarboxylic acid (TCA) cycle to maintain the proliferative advantage of UGCG overexpressing cells. Our data reveal a link between GSL and glutamine metabolism in breast cancer cells, which is to our knowledge a novel correlation in the field of sphingolipid research.
Highlights
UDP-glucose ceramide glucosyltransferase (UGCG) is the key enzyme in glycosphingolipid (GSL) metabolism by being the only enzyme that generates glucosylceramide (GlcCer) de novo
GlcCer is the precursor for all GSL and our previous studies showed that UGCG overexpression in MCF-7 cells leads to alterations in the composition of glycosphingolipid-enriched microdomains (GEMs) resulting in increased cell proliferation, nutritional supply was restricted[4]
The proliferative advantage of MCF-7/UGCG OE cells is sustained in low-glucose medium indicating that the increased proliferation is not limited by decreased glucose supply (Fig. 1B)
Summary
UDP-glucose ceramide glucosyltransferase (UGCG) is the key enzyme in glycosphingolipid (GSL) metabolism by being the only enzyme that generates glucosylceramide (GlcCer) de novo. GlcCer is the precursor for all GSL and our previous studies showed that UGCG overexpression in MCF-7 cells leads to alterations in the composition of glycosphingolipid-enriched microdomains (GEMs) resulting in increased cell proliferation, nutritional supply was restricted[4]. Since enhanced proliferation entails increased demand for nutrients to serve as building blocks for macromolecules such as proteins, DNA, RNA and lipids, as well as the carbon source for metabolic energy generation, cancer cells have developed mechanisms to increase nutrient uptake. Our previous results show an increased proliferation of UGCG overexpressing MCF-7 (MCF-7/ UGCG OE) cells in an environment with reduced nutritional supply[4] This was accompanied by doxorubicin resistance and induction of anti-apoptotic genes, which is presumably mediated by an altered composition of GEMs and AKT and ERK1/2 signaling pathway induction[4]. The revealed cellular mechanisms give new insights into the role of the UGCG in cancer cell energy metabolism and may contribute to better understanding of cancer cell adaption to poor nutritional supply
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