Functional Roles Of Glycosphingolipids In Drug-Resistance Of Human Acute Myeloid Leukemia

Acute myeloid leukemia(AML), the most common type of leukemia in adults, has the lowest survival rate among all leukemias. Multidrug resistance(MDR) is a major challenge to the successful treatment of AML. Nowadays, many researchers are struggling to adequately evaluate the relationship between glycan alterations and resistance to chemotherapy of cancer cells. However, there is still little information about the role of glycosphingolipids(GSLs) in the development of leukemia MDR. This study investigated GSLs on MDR in AML HL60 and HL60/adriamycin-resistant(ADR) cells.Using thin layer chromatography(TLC) and mass spectrometry(MS) analysis, the composition profiling of GSLs differed in two cell lines. Lacto/neolacto-series GSLs(Lc3, n Lc4, Fuc-nLc4) and ganglio-series GSLs(GM2, GM1) were highly expressed in HL60 and HL60/ADR cells, respectively. Besides, NeuGc modified gangliosides(GM2, GM1) were found in HL60/ADR cells and overexpressed. Real-time PCR showed the differential expressional profiles of glycosyltransferase(GTase) genes in two cell lines. β3GNT5(Lc3 synthetase) and β4GALNT1(GM2 synthetase) were overexpressed in HL60 and HL60/ADR cells, respectively. The altered level of lacto/neolacto-series GSLs by up-regulating β3GNT5 expression could increase drug sensitivity of HL60/ADR cells. Further data demonstrated that regulation of lacto/neolacto-series GSLs expression influenced the formation of glycosphingolipids-enriched microdomain(GEM) to modulate the activity of phosphoinositide-3 kinase(PI3K) /Akt signaling pathway and its downstream targets thus regulate cell survival or the expression of P-glycoprotein(P-gp) and MDR-related protein 1(MRP1), both of which are known to be involved in MDR.GSLs may play a critical role of the development of leukemia MDR. Targeting lacto/neolacto-series GSLs(Lc3, nLc4, Fuc-nLc4) could be a novel strategy to reverse or treat AML multidrug resistance.