UDP-glucose ceramide glucosyltransferase activates AKT, promoted proliferation, and doxorubicin resistance in breast cancer cells

A1 Journal article (refereed)


Internal Authors/Editors


Publication Details

List of Authors: Marthe-Susanna Wegner, Nina Schömel, Lisa Gruber, Stephanie Beatrice Örtel, Matti Aleksi Kjellberg, Peter Mattjus, Jennifer Kurz, Sandra Trautmann, Bing Peng, Martin Wegner, Manuel Kaulich, Robert Ahrends, Gerd Geisslinger, Sabine Grösch
Publisher: Springer
Publication year: 2018
Journal: Cellular and Molecular Life Sciences
Journal acronym: CELL MOL LIFE SCI
Volume number: 75
Issue number: 18
Start page: 3393
End page: 3410
Number of pages: 18
ISSN: 1420-682X
eISSN: 1420-9071


Abstract

The UDP-glucose ceramide glucosyltransferase (UGCG) is a key enzyme in the synthesis of glycosylated sphingolipids, since this enzyme generates the precursor for all complex glycosphingolipids (GSL), the GlcCer. The UGCG has been associated with several cancer-related processes such as maintaining cancer stem cell properties or multidrug resistance induction. The precise mechanisms underlying these processes are unknown. Here, we investigated the molecular mechanisms occurring after UGCG overexpression in breast cancer cells. We observed alterations of several cellular properties such as morphological changes, which enhanced proliferation and doxorubicin resistance in UGCG overexpressing MCF-7 cells. These cellular effects seem to be mediated by an altered composition of glycosphingolipid-enriched microdomains (GEMs), especially an accumulation of globotriaosylceramide (Gb3) and glucosylceramide (GlcCer), which leads to an activation of Akt and ERK1/2. The induction of the Akt and ERK1/2 signaling pathway results in an increased gene expression of multidrug resistance protein 1 (MDR1) and anti-apoptotic genes and a decrease of pro-apoptotic gene expression. Inhibition of the protein kinase C (PKC) and phosphoinositide 3 kinase (PI3K) reduced MDR1 gene expression. This study discloses how changes in UGCG expression impact several cellular signaling pathways in breast cancer cells resulting in enhanced proliferation and multidrug resistance.


Keywords

Apoptotic, Glycosphingolipid-enriched microdomains, MDR1, multidrug resistance

Last updated on 2019-17-10 at 03:00