Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 75, Issue 18, Pages 3393-3410Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-018-2799-7
Keywords
Glycosphingolipids; Glycosphingolipid-enriched microdomains; Multidrug resistance; MDR1; Glucosylceramide; Apoptotic
Categories
Funding
- Deutsche Forschungsgemeinschaft [WE 5825/1-1]
- SFB [1039 TP B05]
- August Scheidel-Stiftung
- Heinrich und Fritz Riese-Stiftung
- Minerva-Stiftung
- Ministerium fur Innovation
- Ministerium fur Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen
- Senatsverwaltung fur Wirtschaft, Technologie und Forschung des Landes Berlin
- Bundesministerium fur Bildung und Forschung
- BMBF [031L0108A, 031A534B]
- Sigrid Juselius Foundation
- Magnus Ehrnrooth Foundation
- Abo Akademi University
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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.
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