Increased glucosylceramide production leads to decreased cell energy metabolism and lowered tumor marker expression in non-cancerous liver cells

Marthe-Susanna Wegner,Kyle L Hoehn,Nerea Ferreirós,Frances L Byrne,Andreas Weigert,Ellen M Olzomer,Nina Schömel,Gerd Geisslinger,Catherine Olesch,Robert Gurke,Sandra Trautmann,Bernhard Brüne

doi:10.1007/s00018-021-03958-9

Abstract

Hepatocellular carcinoma (HCC) is one of the most difficult cancer types to treat. Liver cancer is often diagnosed at late stages and therapeutic treatment is frequently accompanied by development of multidrug resistance. This leads to poor outcomes for cancer patients. Understanding the fundamental molecular mechanisms leading to liver cancer development is crucial for developing new therapeutic approaches, which are more efficient in treating cancer. Mice with a liver specific UDP-glucose ceramide glucosyltransferase (UGCG) knockout (KO) show delayed diethylnitrosamine (DEN)-induced liver tumor growth. Accordingly, the rationale for our study was to determine whether UGCG overexpression is sufficient to drive cancer phenotypes in liver cells. We investigated the effect of UGCG overexpression (OE) on normal murine liver (NMuLi) cells. Increased UGCG expression results in decreased mitochondrial respiration and glycolysis, which is reversible by treatment with EtDO-P4, an UGCG inhibitor. Furthermore, tumor markers such as FGF21 and EPCAM are lowered following UGCG OE, which could be related to glucosylceramide (GlcCer) and lactosylceramide (LacCer) accumulation in glycosphingolipid-enriched microdomains (GEMs) and subsequently altered signaling protein phosphorylation. These cellular processes lead to decreased proliferation in NMuLi/UGCG OE cells. Our data show that increased UGCG expression itself does not induce pro-cancerous processes in normal liver cells, which indicates that increased GlcCer expression leads to different outcomes in different cancer types.Graphic abstract

Highlights

The most frequent type of primary liver cancer is hepatocellular carcinoma (HCC), which is characterized by transformation of liver cells into tumor cells
First we investigated the effect of an UDP-glucose ceramide glucosyltransferase (UGCG) OE on liver cell metabolism
Basal mitochondrial respiration is significantly decreased in normal murine liver (NMuLi)/UGCG OE cells compared to control cells (Fig. 1C, S1B)

Summary

Introduction

The most frequent type of primary liver cancer is hepatocellular carcinoma (HCC), which is characterized by transformation of liver cells into tumor cells. In 2018, lenvatinib ( a multikinase inhibitor) was approved from the Food and Drug Administration (FDA) as a first-line treatment of patients with unresectable HCC (reviewed in [13]). Combination therapy with atezolizumab and bevacizumab provides superior outcome for the patients compared with sorafenib, but the incidence of serious adverse events is increased (reviewed in [32]). Despite these novel therapeutic approaches, for many of the HCC patients only palliative care applies. This reveals the importance of investigating the molecular mechanisms of HCC development. By adding a galactose molecule to GlcCer, Increased glucosylceramide production leads to decreased cell energy metabolism and lowered

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Discussion

Conclusion