Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differentially modulating ABC transporters in chronic myeloid leukemias

Abstract

Multidrug resistance (MDR) in cancer arises from cross-resistance to structurally- and functionally-divergent chemotherapeutic drugs. In particular, MDR is characterized by increased expression and activity of ATP-binding cassette (ABC) superfamily transporters. Sphingolipids are substrates of ABC proteins in cell signaling, membrane biosynthesis, and inflammation, for example, and their products can favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key regulatory enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Stressed cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after UGCG mediates incorporation into GlcCer. Given that cancer cells seem to mobilize UGCG and have increased GSL content for ceramide clearance, which ultimately contributes to chemotherapy failure, here we investigated how inhibition of GSL biosynthesis affects the MDR phenotype of chronic myeloid leukemias. We found that MDR is associated with higher UGCG expression and with a complex GSL profile. UGCG inhibition with the ceramide analog d-threo-1-(3,4,-ethylenedioxy)phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4) greatly reduced GSL and monosialotetrahexosylganglioside levels, and co-treatment with standard chemotherapeutics sensitized cells to mitochondrial membrane potential loss and apoptosis. ABC subfamily B member 1 (ABCB1) expression was reduced, and ABCC-mediated efflux activity was modulated by competition with nonglycosylated ceramides. Consistently, inhibition of ABCC-mediated transport reduced the efflux of exogenous C6-ceramide. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, which typically overcomes drug resistance through distinct mechanisms. This work sheds light on the involvement of GSL in chemotherapy failure, and its findings suggest that targeted GSL modulation could help manage MDR leukemias.

The Phenoxyphenol Compound diTFPP Mediates Exogenous C2-Ceramide Metabolism, Inducing Cell Apoptosis Accompanied by ROS Formation and Autophagy in Hepatocellular Carcinoma Cells

“…UGCG has been reported to be a regulator of Akt activation and a promoter of cell proliferation [ 48 ]. Salustiano and Previato also discovered that UGCG is involved in multidrug resistance [ 49 ]. The synthesis of ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P) is associated with ceramide kinase (CERK) and sphingosine kinase (SPHK), which phosphorylate ceramide and sphingosine, respectively [ 50 ].…”

Gut Microbiota Combined With Metabolomics Reveals the Repeated Dose Oral Toxicity of β-Cyclodextrin in Mice

“…Pathways including ABC transporters, pyrimidine metabolism, purine metabolism, glucagon signaling, insulin signaling, glycolysis/gluconeogenesis and NAFLD were enriched by analysis of differential metabolites. ABC transporters mediate the ATP-dependent cellular export of a plethora of toxic metabolites and xenobiotic substances, and play key roles in multidrug resistance ( Salustiano et al, 2020 ; Xiao et al, 2020 ). Dysregulation of the ABC transporters pathway indicates that animals might be under toxic stress after exposure to β-CD.…”

Integration of Sugar Metabolism and Proteoglycan Synthesis by UDP-glucose Dehydrogenase

“…Inhibition of UGDH would be expected to increase UDP-glucose signaling through P2Y14, the effect of which is microenvironment dependent, but includes the induction of osteoclast formation in conjunction with RANKL, 60 stimulation of macrophages in the acute inflammatory response through STAT1 phosphorylation and potentiation of RARβ signaling, 61 and aggravation of ischemic acute kidney injury in cardiac surgery patients. 62 UDP-glucose increases are also known to provide a substrate for the enzyme UDP-glucose ceramide glucosyltransferase, which is a component of sphingolipid metabolism that mitigates ceramide toxicity normally, but promotes therapeutic resistance in chronic myeloid leukemia 63 and alters metabolic fuel dependence in breast cancer. 64 In conclusion, increased numbers of associations have been reported between the function of UGDH, its inter-subunit contacts, and its heterologous proteinprotein interactions, which supports a role for UGDH in prioritizing metabolite distribution among its critical downstream pathways.…”