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Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differentially modulating ABC transporters in chronic myeloid leukemias.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2020 May 08; Vol. 295 (19), pp. 6457-6471. Date of Electronic Publication: 2020 Mar 30. - Publication Year :
- 2020
-
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 C <subscript>6</subscript> -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.<br /> (© 2020 Salustiano et al.)
- Subjects :
- ATP-Binding Cassette Transporters genetics
Glucosyltransferases antagonists & inhibitors
Glucosyltransferases genetics
Glucosyltransferases metabolism
Glycosphingolipids genetics
Humans
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology
Neoplasm Proteins genetics
Propanolamines pharmacology
Pyrrolidines pharmacology
ATP-Binding Cassette Transporters metabolism
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Glycosphingolipids blood
Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism
Neoplasm Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 295
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32229586
- Full Text :
- https://doi.org/10.1074/jbc.RA120.013090