Journal Article

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

Geisslinger, Gerd, Kaulich, Manuel, Trautmann, Sandra, Kurz, Jennifer, Wegner, Marthe-Susanna, Peng, Bing, Grösch, Sabine, Örtel, Stephanie Beatrice, Mattjus, Peter, Kjellberg, Matti Aleksi, Schömel, Nina, Gruber, Lisa, Ahrends, Robert, Wegner, Martin

2018

Overview

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.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: 1-Phosphatidylinositol 3-kinase / AKT protein / Apoptosis / Apoptosis - genetics / ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics / ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism / Biochemistry / Biomedical and Life Sciences / Biomedicine / Breast cancer / breast neoplasms / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer / Cell Biology / Cell Proliferation / Ceramide / Ceramide glucosyltransferase / Cholesterol - analysis / Doxorubicin / Doxorubicin - pharmacology / Drug Resistance, Neoplasm - genetics / Enzymes / Extracellular signal-regulated kinase / Female / Gems / Gene expression / genes / Globotriaosylceramide / Glucose / glucosylceramides / Glucosyltransferase / Glucosyltransferases - genetics / Glucosyltransferases - metabolism / Glycosphingolipids / glycosylation / Humans / Kinases / Life Sciences / MCF-7 Cells / MDR1 protein / Mitogen-Activated Protein Kinase 1 - metabolism / Mitogen-Activated Protein Kinase 3 - metabolism / Molecular modelling / Multidrug resistance / Multidrug resistant organisms / multiple drug resistance / neoplasm cells / Original / Original Article / P-Glycoprotein / P-glycoproteins / phosphatidylinositol 3-kinase / Phosphatidylinositol 3-Kinases - metabolism / Phosphoinositide-3 Kinase Inhibitors / Protein kinase C / Protein Kinase C - antagonists & inhibitors / Protein Kinase C - metabolism / Proteins / Proto-Oncogene Proteins c-akt - metabolism / Signal transduction / Signal Transduction - genetics / Signaling / Sphingolipids / Sphingolipids - analysis / Sphingolipids - metabolism / Sphingomyelin Phosphodiesterase - genetics / Sphingomyelin Phosphodiesterase - metabolism / Sphingosine N-Acyltransferase - genetics / Sphingosine N-Acyltransferase - metabolism / Stem cells