UDP-glucose ceramide glucosyltransferase activates AKT, promoted proliferation, and doxorubicin resistance in breast cancer cells
UDP-glucose ceramide glucosyltransferase activates AKT, promoted proliferation, and doxorubicin resistance in breast cancer cells
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DOI：
10.1007/s00018-018-2799-7
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发表时间：
2018-03
影响因子：
8
通讯作者：
Marthe-Susanna Wegner;Nina Schömel;L. Gruber;Stephanie Beatrice Örtel;M. Kjellberg;P. Mattjus;Jennifer Kurz;S. Trautmann;B. Peng;Martin Wegner;M. Kaulich;R. Ahrends;G. Geisslinger;S. Grösch
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文献类型：
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作者：
Marthe-Susanna Wegner;Nina Schömel;L. Gruber;Stephanie Beatrice Örtel;M. Kjellberg;P. Mattjus;Jennifer Kurz;S. Trautmann;B. Peng;Martin Wegner;M. Kaulich;R. Ahrends;G. Geisslinger;S. Grösch
UDP-葡萄糖神经酰胺葡萄糖基转移酶 (UGCG) 是糖基化鞘脂合成中的关键酶，因为该酶生成所有复杂鞘糖脂 (GSL) 的前体，即 GlcCer。 UGCG 与多种癌症相关过程有关，例如维持癌症干细胞特性或诱导多药耐药性。这些过程背后的确切机制尚不清楚。在这里，我们研究了乳腺癌细胞中 UGCG 过度表达后发生的分子机制。我们观察到多种细胞特性的改变，例如形态变化，这增强了 UGCG 过表达 MCF-7 细胞的增殖和阿霉素耐药性。这些细胞效应似乎是由富含鞘糖脂的微结构域 (GEM) 组成的改变介导的，尤其是三糖神经酰胺 (Gb3) 和葡萄糖神经酰胺 (GlcCer) 的积累，导致 Akt 和 ERK1/2 的激活。 Akt 和 ERK1/2 信号通路的诱导导致多药耐药蛋白 1 (MDR1) 和抗凋亡基因的基因表达增加，以及促凋亡基因表达的减少。抑制蛋白激酶C（PKC）和磷酸肌醇3激酶（PI3K）可降低MDR1基因表达。这项研究揭示了 UGCG 表达的变化如何影响乳腺癌细胞中的几种细胞信号传导途径，从而导致增殖和多药耐药性增强。
TheUDP-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 ofglobotriaosylceramide(Gb3) andglucosylceramide(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 ofmultidrug resistance protein 1(MDR1) and anti-apoptotic genes and a decrease of pro-apoptotic gene expression. Inhibition of theprotein kinase C(PKC) andphosphoinositide 3 kinase(PI3K) reducedMDR1gene 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.