UGCG overexpression leads to increased glycolysis and increased oxidative phosphorylation of breast cancer cells

Nina Schömel,Marthe-Susanna Wegner,Nerea Ferreirós,Ellen M Olzomer,Frances L Byrne,Lisa Gruber,Dominique Thomas,Stephanie J Alexopoulos,Gerd Geisslinger,Robert Gurke,Sandra Trautmann,Kyle L Hoehn

doi:10.1038/s41598-020-65182-y

Abstract

The only enzyme in the glycosphingolipid (GSL) metabolic pathway, which produces glucosylceramide (GlcCer) de novo is UDP-glucose ceramide glucosyltransferase (UGCG). UGCG is linked to pro-cancerous processes such as multidrug resistance development and increased proliferation in several cancer types. Previously, we showed an UGCG-dependent glutamine metabolism adaption to nutrient-poor environment of breast cancer cells. This adaption includes reinforced oxidative stress response and fueling the tricarboxylic acid (TCA) cycle by increased glutamine oxidation. In the current study, we investigated glycolytic and oxidative metabolic phenotypes following UGCG overexpression (OE). UGCG overexpressing MCF-7 cells underwent a metabolic shift from quiescent/aerobic to energetic metabolism by increasing both glycolysis and oxidative glucose metabolism. The energetic metabolic phenotype was not associated with increased mitochondrial mass, however, markers of mitochondrial turnover were increased. UGCG OE altered sphingolipid composition of the endoplasmic reticulum (ER)/mitochondria fractions that may contribute to increased mitochondrial turnover and increased cell metabolism. Our data indicate that GSL are closely connected to cell energy metabolism and this finding might contribute to development of novel therapeutic strategies for cancer treatment.

Highlights

The only enzyme in the glycosphingolipid (GSL) metabolic pathway, which produces glucosylceramide (GlcCer) de novo is UDP-glucose ceramide glucosyltransferase (UGCG)
The basal mitochondrial respiration, which is represented by oxygen consumption rate (OCR), was significantly increased in MCF-7/UGCG OE cells as compared to control cells (Fig. 1B,C)
We detected a significant increase of the mRNA level of mitofusin 1 (MFN1) in MCF-7/ UGCG OE cells, whereas mitofusin 2 (MFN2) mRNA expression was unchanged (Fig. 3A)

Summary

Introduction

The only enzyme in the glycosphingolipid (GSL) metabolic pathway, which produces glucosylceramide (GlcCer) de novo is UDP-glucose ceramide glucosyltransferase (UGCG). We showed an UGCG-dependent glutamine metabolism adaption to nutrient-poor environment of breast cancer cells This adaption includes reinforced oxidative stress response and fueling the tricarboxylic acid (TCA) cycle by increased glutamine oxidation. Previous studies revealed that UDP-glucose ceramide glucosyltransferase (UGCG) overexpression (OE) leads to alterations of GEM composition in breast cancer cells resulting in signaling pathway activation and subsequently altered gene expression[6]. We were able to show that glutamine is used for reinforced oxidative stress response via glutathione production and fuels the TCA cycle to sustain the proliferative advantage of UGCG overexpressing breast cancer cells[22]. Our data indicate that GSL are closely connected to cell energy metabolism, which is to our knowledge a novel finding This finding might contribute to development of novel therapeutic strategies for cancer treatment

Methods

Results

Conclusion