Abstract
The UDP-glucose ceramide glycosyltransferase (UGCG) is a key enzyme in the sphingolipid metabolism by generating glucosylceramide (GlcCer), the precursor for all glycosphingolipids (GSL), which are essential for proper cell function. Interestingly, the UGCG is also overexpressed in several cancer types and correlates with multidrug resistance protein 1 (MDR1) gene expression. This membrane protein is responsible for efflux of toxic substances and protects cancer cells from cell damage through chemotherapeutic agents. Studies showed a connection between UGCG and MDR1 overexpression and multidrug resistance development, but the precise underlying mechanisms are unknown. Here, we give an overview about the UGCG and its connection to MDR1 in multidrug resistant cells. Furthermore, we focus on UGCG transcriptional regulation, the impact of UGCG on cellular signaling pathways and the effect of UGCG and MDR1 on the lipid composition of membranes and how this could influence multidrug resistance development. To our knowledge, this is the first review presenting an overview about UGCG with focus on the relationship to MDR1 in the process of multidrug resistance development.
Highlights
Over the last two decades, researchers were able to link the sphingolipid metabolism and the development of multidrug resistance in several cancer types, but the precise mechanisms are unknown
There is evidence that the UDP-glucose ceramide glycosyltransferase (UGCG), which is located in the Golgi apparatus (Fig. 4) is involved in the process of multidrug resistance development
Receptor trimerization and activation of the protein Factor associated with activation of neutral sphingomyelinase (SMase) (FAN) that binds to the intracellular neutral SMase domain (NSD), thereby activating the neutral SMase, occurs
Summary
Over the last two decades, researchers were able to link the sphingolipid metabolism and the development of multidrug resistance in several cancer types, but the precise mechanisms are unknown. Nude mice studies showed that silencing the UGCG gene in adriamycin-resistant MCF-7 cells, which overexpress the UGCG, inhibits tumor xenograft growth in vivo [12]. Gouazé et al showed that this is not a unique phenomenon for breast cancer cells, because several other cancer cells e.g. human leukemia and colon cancer cells, exhibit a high UGCG gene expression [17] This overexpression correlates with increased multidrug resistance protein 1 (MDR1) gene expression, which encodes the protein P-glycoprotein 1 (P-gp) The P-gp protein expressed at the plasma and Golgi membrane plays an important role in multidrug resistance by transporting toxic substances out of the cell (reviewed in [19]) (Fig. 4). In the case of the intrinsic apoptotic pathway, which recently was shown to be mediated by a mitochondria-specific ceramide pool (reviewed in [24]), the residence of the UGCG in the Golgi apparatus seems to prohibit ceramide clearance
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