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UDP-Glucose Ceramide Glucosyltransferase Activates AKT, Promoted Proliferation, and Doxorubicin Resistance in Breast Cancer Cell

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UDP-Glucose Ceramide Glucosyltransferase Activates AKT, Promoted Proliferation, and Doxorubicin Resistance in Breast Cancer Cell Cellular and Molecular Life Sciences https://doi.org/10.1007/s00018-018-2799-7 Cellular andMolecular Life Sciences ORIGINAL ARTICLE UDP‑glucose ceramide glucosyltransferase activates AKT, promoted proliferation, and doxorubicin resistance in breast cancer cells Marthe‑Susanna Wegner1 · Nina Schömel1 · Lisa Gruber1 · Stephanie Beatrice Örtel1 · Matti Aleksi Kjellberg2 · Peter Mattjus2 · Jennifer Kurz3 · Sandra Trautmann1 · Bing Peng4 · Martin Wegner5 · Manuel Kaulich5 · Robert Ahrends4 · Gerd Geisslinger1,3 · Sabine Grösch1 Received: 5 October 2017 / Revised: 19 February 2018 / Accepted: 13 March 2018 © Springer International Publishing AG, part of Springer Nature 2018 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 asso- ciated with several cancer-related processes such as maintaining cancer stem cell properties or multidrug resistance induc- tion. 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 efects 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 Glycosphingolipids · Glycosphingolipid-enriched microdomains · Multidrug resistance · MDR1 · Glucosylceramide · Apoptotic Introduction the fundamental cellular processes in breast (cancer) cells, which are leading, for example, to promoted proliferation In the year 2015, breast cancer was declared as the second and multidrug resistance development. Multidrug resist- leading cause of cancer death in women in industrial coun- ance of cancer cells is the main cause of therapy failure. It tries [1]. This fact underlines the importance to investigate is accomplished by alteration of myriad cellular signaling cascades resulting, for example, in enhanced expression of multidrug resistance proteins, which transport toxic sub- Electronic supplementary material The online version of this stances out of cancer cells. article (https​://doi.org/10.1007/s0001​8-018-2799-7) contains supplementary material, which is available to authorized users. * Marthe‑Susanna Wegner 3 Fraunhofer Institute for Molecular Biology and Applied [email protected]‑frankfurt.de Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Frankfurt am Main, Germany 1 pharmazentrum frankfurt/ZAFES, Institute of Clinical 4 Leibniz-Institut für Analytische Wissenschaften, ISAS e. V., Pharmacology, Johann Wolfgang Goethe University, Otto‑Hahn‑Straße 6b, 44227 Dortmund, Germany House 74, Theodor Stern‑Kai 7, 60590 Frankfurt am Main, Germany 5 Institute of Biochemistry II, Johann Wolfgang Goethe University, Theodor Stern‑Kai 7, 60590 Frankfurt am Main, 2 Biochemistry, Faculty of Science and Engineering, Åbo Germany Akademi University, Artillerigatan 6A, III, BioCity, 20520 Turku, Finland Vol.:(0123456789)1 3 M.-S. Wegner et al. The UDP-glucose ceramide glucosyltransferase (UGCG) the Golgi apparatus where they are used for the synthesis was frst cloned by Ichikawa et al. [2] and is connected to of sphingomyelin (constituted of ceramide and phospho- processes of multidrug resistance in cancer cells. This in choline or a phosphoethanolamine group) or cerebrosides the cis-Golgi apparatus residing protein transfers a glucose (Fig. 1). Subsequently, cerebrosides can be used as precur- moiety in β-linkage to the position 1 hydroxyl group of cera- sors for synthesis of lactosylceramides (LacCer), which are mide, which results in glucosylceramide (GlcCer) formation also named globosides. Globosides can be metabolized to (Fig. 1). GlcCer, also named cerebrosides, serve as precur- gangliosides. sors for all complex glycosphingolipids (GSLs). Ceramides, Knockout of the UGCG in mice leads to embryonic which are used for GlcCer synthesis, are produced in the lethality during the phase of gastrulation [4]. In addi- endoplasmic reticulum by six mammalian ceramide syn- tion, a constitutive disruption of this protein in mice epi- thase (CerS) isoforms, which have a substrate specifcity dermis results in loss of skin barrier function and death for acyl-CoenzymeAs (acyl-CoAs) of defned chain length due to dehydration [5]. Amen et al. showed that GlcCer [3]. Accordingly, each CerS isoform produces ceramide spe- is essential for proper formation of the lamellar body, cies of a specifc chain length. Ceramides are transported to regular metabolism, and composition of lipids in the Fig. 1 Schematic overview of the potential mechanisms of UGCG- membrane protein activities and activation of signaling pathways like derived GSLs infuencing membrane lipid composition resulting Akt and ERK1/2. Activation of these kinases increases proliferation in cellular signaling pathway induction. Overexpression of UGCG and MDR1 expression. GSL glycosphingolipid, GEM glycosphin- results in increased GlcCer concentration leading to Gb3 accumu- golipid-enriched microdomain, P-gp P-glycoprotein, bis I bisindolyl- lation and augmented integration of GlcCer in plasma membrane maleimide I, PKC protein kinase C, PI3K phosphoinositide 3-kinase structures. This results in altered biophysical membrane properties of (PI3K) glycosphingolipid-enriched microdomains (GEMs), which may alter 1 3 UDP-glucose ceramide glucosyltransferase activates AKT, promoted proliferation, and… stratum corneum [6]. All these parameters are important Results for maintaining water permeability function. Deletion of the UGCG in nervous system-specifc cells leads to Establishing a stably UGCG overexpressing MCF‑7 disturbance of brain tissue by the loss of Purkinje cells cell line (reviewed in [7]). Moreover, long-term pharmacological inhibition of the UGCG with eliglustat in patients with MCF-7 cells were transfected with an UGCG expression Gaucher disease type 1 was well tolerated [8]. plasmid (MCF-7/UGCG OE) or a control vector (MCF-7/ The UGCG is overexpressed in several cancer types, for pTarget) (MCF-7/naiv = no transfection). After selec- example, in metastatic breast cancer tissue resulting in a tion of the cells with G418 over several weeks, UGCG poor patient prognosis [9] and colon cancer cells [10]. This mRNA and protein expression was analyzed. Figure 2a overexpression correlates with an enhanced expression of shows a signifcantly increased UGCG mRNA expression P-glycoprotein 1 (P-gp) (also ATP-binding cassette sub- in MCF-7/UGCG OE cells as compared to MCF-7/naiv family B member 1, ABCB1), which is encoded by the mul- and MCF-7/pTarget cells. This is verifed at protein level tidrug resistance protein 1 (MDR1) gene. The exact molecu- by Western blot analysis (Fig. 2b). In addition, the UGCG lar mechanisms by which UGCG and MDR1 are connected overexpression in MCF-7/UGCG OE cells was confrmed are unknown, but it could be shown that MDR1 regulates by immunocytochemistry (Fig. 2c). In all three MCF-7 UGCG promoter activity as well as UGCG regulates MDR1 cell types, UGCG co-localizes with GM130, a marker for expression (reviewed in [11–13]). Liu et al. showed that the cis-Golgi apparatus. In summary, the overexpression globo-series GSL produced by UGCG activity alter MDR1 of UGCG protein in MCF-7/UGCG cells has been shown. expression [14]. Overexpression of UGCG in combination with chemotherapeutic agents leads to increased Gb3 and Gb5 concentrations in GSL-enriched microdomains (GEM). Morphological and physiological changes This results in cSrc tyrosine kinase activation, decreased following UGCG overexpression β-catenin phosphorylation, and increased nuclear β-catenin. It is assumed that nuclear β-catenin may bind in a com- Overexpression of UGCG in MCF-7 cells leads to an plex with the T-cell factor 4 (Tcf4) to the Tcf4/lymphoid enlarged cytoplasm as compared to control cells (Fig. 3a). enhancer factor (LEF) binding motif at the MDR1 pro- In addition, MCF-7/UGCG OE cells exhibit an up to 70% moter and thus enhancing promoter activity. This leads to increased nucleus size as quantifed by calculating the enhanced P-gp expression and subsequently to efux of anti- nucleus-to-cytoplasm (N:C) ratio in the diferent MCF-7 cancer drugs from cells. P-gp is also postulated to function cells (Fig. 3b). This ratio is defned as the ratio of the as a fippase, transporting GlcCer from the outer to the inner nuclear area divided by the cytoplasmic area indicating leafet of the Golgi apparatus, where it can be metabolized to abnormal nuclear morphology. MCF-7/UGCG OE cells more complex sphingolipids like GSLs (reviewed in [15]). exhibit also a promoted proliferation indicated by a fve- The regulation of the UGCG is rarely
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