TY  - JOUR
A1  - Wegner, Marthe-Susanna
A1  - Schömel, Nina
A1  - Olzomer, Ellen M.
A1  - Trautmann, Sandra
A1  - Olesch, Catherine
A1  - Byrne, Frances L.
A1  - Brüne, Bernhard
A1  - Gurke, Robert
A1  - Ferreirós Bouzas, Nerea
A1  - Weigert, Andreas
A1  - Geisslinger, Gerd
A1  - Hoehn, Kyle L.
T1  - Increased glucosylceramide production leads to decreased cell energy metabolism and lowered tumor marker expression in non-cancerous liver cells
T2  - Cellular and molecular life sciences
N2  - 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.
KW  - Glycolysis
KW  - Oxidative phosphorylation
KW  - Mitochondrial ROS
KW  - HCC marker
KW  - GEMs
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/69566
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-695668
SN  - 1420-9071
N1  - Open Access funding enabled and organized by Projekt DEAL. This work was funded by the Deutsche Forschungsgemeinschaft (WE 5825/2-1 and CRC 1039, TP B04, B06, Z01).
VL  - 78
IS  - 21-22
SP  - 7025
EP  - 7041
PB  - Springer International Publishing AG
CY  - Cham (ZG)
ER  -