Abstract
β-1, 4-Galactosyltransferase gene (B4GALT) family consists of seven members, which encode corresponding enzymes known as type II membrane-bound glycoproteins. These enzymes catalyze the biosynthesis of different glycoconjugates and saccharide structures, and have been recognized to be involved in various diseases. In this study, we sought to determine the expressional profiles of B4GALT family in four pairs of parental and chemoresistant human leukemia cell lines and in bone marrow mononuclear cells (BMMC) of leukemia patients with multidrug resistance (MDR). The results revealed that B4GALT1 and B4GALT5 were highly expressed in four MDR cells and patients, altered levels of B4GALT1 and B4GALT5 were responsible for changed drug-resistant phenotype of HL60 and HL60/adriamycin-resistant cells. Further data showed that manipulation of these two gene expression led to increased or decreased activity of hedgehog (Hh) signaling and proportionally mutative expression of p-glycoprotein (P-gp) and MDR-associated protein 1 (MRP1) that are both known to be related to MDR. Thus, we propose that B4GALT1 and B4GALT5, two members of B4GALT gene family, are involved in the development of MDR of human leukemia cells, probably by regulating the activity of Hh signaling and the expression of P-gp and MRP1.
Highlights
Glycosyltransferases (GTs) catalyze the transfer of sugar moieties from activated donor molecules to specific acceptor molecules that determines the biosynthesis of glycans
We previously identified that B4GALT1 gene enhanced the activity of Hh signaling and promoted multidrug resistance (MDR) in K562/ adriamycin-resistant (ADR) cell line.[25]
We carried on the studies in order to investigate the association between the B4GALT family and MDR of human leukemia cells
Summary
Glycosyltransferases (GTs) catalyze the transfer of sugar moieties from activated donor molecules to specific acceptor molecules that determines the biosynthesis of glycans. The key signal molecules of Hh network are recognized as oncogenes, such as smoothened (Smo), sonic hedgehog (Shh) and glioma-associated oncogene (Gli-1).[19] several reports indicate that aberrant activation of Hh pathway leads to the survival and drug resistance of different types of human cancer cells.[20] Specific inhibition of the Hh pathway may be an effective therapeutic strategy for overcoming treatment resistance of malignant tumors, for example, upregulation of Gli-1 is correlated with glioma recurrence after chemotherapy, and blocking the Hh pathway activity elevates chemosensitivity of glioma cells.[21] In leukemic cells, chemoresistance is shown to be maintained by Hh signaling activation, and could be reversed by cyclopamine, a known Hh antagonist.[22]
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