Abstract
P-glycoprotein (P-gp), also known as ABCB1, is a member of the ABC transporter family of proteins. P-gp is an ATP-dependent drug efflux pump that is localized to the plasma membrane of mammalian cells and confers multidrug resistance in neoplastic cells. P-gp is a 140-kDa polypeptide that is glycosylated to a final molecular weight of 170 kDa. Our experimental model used two variants of L1210 cells in which overexpression of P-gp was achieved: either by adaptation of parental cells (S) to vincristine (R) or by transfection with the human gene encoding P-gp (T). R and T cells were found to differ from S cells in transglycosylation reactions in our recent studies. The effects of tunicamycin on glycosylation, drug efflux activity and cellular localization of P-gp in R and T cells were examined in the present study. Treatment with tunicamycin caused less concentration-dependent cellular damage to R and T cells compared with S cells. Tunicamycin inhibited P-gp N-glycosylation in both of the P-gp-positive cells. However, tunicamycin treatment did not alter either the P-gp cellular localization to the plasma membrane or the P-gp transport activity. The present paper brings evidence that independently on the mode of P-gp expression (selection with drugs or transfection with a gene encoding P-gp) in L1210 cells, tunicamycin induces inhibition of N-glycosylation of this protein, without altering its function as plasma membrane drug efflux pump.
Highlights
P-glycoprotein (P-gp), known as ABCB1, is a member of the ABC transporter family of proteins, and it is an integral protein of the plasma membrane of animal cells [1]
When expressed in neoplastic tissue, P-gp represents a real obstacle for effective chemotherapy of neoplastic diseases, and tissues with increased P-gp are most often observed with the multidrug resistance (MDR) phenotype [2]
The known substrates of this protein represent a large group of unrelated substances, including vincristine, doxorubicin, mitomycin C, actinomycin D, cyclophosphamide and dexamethasone [3]. This protein encoded by the mdr1 gene is first synthesized as a 140-kDa polypeptide precursor that is later glycosylated to a final molecular weight of 170 kDa [4,5]
Summary
P-glycoprotein (P-gp), known as ABCB1, is a member of the ABC transporter family of proteins, and it is an integral protein of the plasma membrane of animal cells [1]. The known substrates of this protein represent a large group of unrelated substances, including vincristine, doxorubicin, mitomycin C, actinomycin D, cyclophosphamide and dexamethasone [3] This protein encoded by the mdr (abcb1) gene is first synthesized as a 140-kDa polypeptide precursor that is later glycosylated to a final molecular weight of 170 kDa [4,5]. Tunicamycin induced an elevation of P-gp expression (at both the mRNA and protein levels) and efflux activity in Fao hepatoma cells [9]. Tunicamycin may induce either an increase or decrease in drug resistance associated with an improvement or impairment of P-gp function, respectively. This dual effect of tunicamycin seems to be due to differences between cell types. In the present study, we examined the effect of tunicamycin on P-gp glycosylation, membrane localization and transport activity
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