A possible role for a mammalian facilitative hexose transporter in the development of resistance to drugs.

Vera, Juan Carlos; Castillo, Gonzalo; Rosen, Ora M.

doi:10.1128/mcb.11.7.3407

Cited by 17 publications

(12 citation statements)

References 68 publications

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“…We have shown that two of them are directly related to the PDR phenomenon. Previous observations have implied relationships between drug resistance and hexose transport processes (11,40). Such a multigene family of glucose transporters closely resembles the mammalian system, six glucose carriers (GLUT) of which have already been identified (20).…”

Section: Discussionmentioning

confidence: 99%

Multiple-Drug-Resistance Phenomenon in the Yeast Saccharomyces cerevisiae: Involvement of Two Hexose Transporters

Nourani

Wésolowski-Louvel

Delaveau

et al. 1997

Molecular and Cellular Biology

110

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In the yeast Saccharomyces cerevisiae, multidrug resistance to unrelated chemicals can result from overexpression of ATP-binding cassette (ABC) transporters such as Pdr5p, Snq2p, and Yor1p. Expression of these genes is under the control of two homologous zinc finger-containing transcription regulators, Pdr1p and Pdr3p. Here, we describe the isolation, by an in vivo screen, of two new Pdr1p-Pdr3p target genes: HXT11 and HXT9. HXT11 and HXT9, encoding nearly identical proteins, have a high degree of identity to monosaccharide transporters of the major facilitator superfamily (MFS). In this study, we show that the HXT11 product, which allows glucose uptake in a glucose permease mutant (rag1) strain of Kluyveromyces lactis, is also involved in the pleiotropic drug resistance process. Loss of HXT11 and/or HXT9 confers cycloheximide, sulfomethuron methyl, and 4-NQO (4-nitroquinoline-N-oxide) resistance. Conversely, HXT11 overexpression increases sensitivity to these drugs in the wild-type strain, an effect which is more pronounced in a strain having both PDR1 and PDR3 deleted. These data show that the two putative hexose transporters Hxt11p and Hxt9p are transcriptionally regulated by the transcription factors Pdr1p and Pdr3p, which are known to regulate the production of ABC transporters required for drug resistance in yeast. We thus demonstrate the existence of genetic interactions between genes coding for two classes of transporters (ABC and MFS) to control the multidrug resistance process.Transmembrane solute transport is ensured in all eukaryotic cells by a set of proteins embedded in the plasma and the internal membranes. Most transport proteins characterized to date catalyze the uptake of solutes across the plasma membrane. Other plasma membrane transporters mediate extrusion of intracellular compounds into the medium, while others, located in intracellular membranes, catalyze efflux from or within the mitochondria, vacuole, peroxisomes, or secretion organelles. These membrane proteins are generally classified in three main categories: channels, facilitators (also named transporters, permeases, or carriers), and pumps (ATPases). Among them, one protein family of particular biological importance is the nonproton ATPase family encoding ATP-binding cassette (ABC) transporters, which appear to be conserved in all living organisms ranging from bacteria to humans (1, 13, 32). Alterations of certain ABC transporters can cause human genetic disorders such as cystic fibrosis (36), Zellweger syndrome (19), X-linked adrenoleukodystrophy (30), and the multidrug-resistance (MDR) phenotype shown by tumor cells which acquire resistance to a variety of chemotherapeutic agents. MDR phenotype is frequently linked to the increased expression, sometimes by gene amplification, of an integral membrane protein, a member of the ABC transporter family. This protein, called P-glycoprotein, functions as an ATP-dependent efflux pump for drugs (18).In the yeast Saccharomyces cerevisiae, a phenotype resembling the mammalian MDR exists and i...

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Section: Discussionmentioning

confidence: 99%

Multiple-Drug-Resistance Phenomenon in the Yeast Saccharomyces cerevisiae: Involvement of Two Hexose Transporters

Nourani

Wésolowski-Louvel

Delaveau

et al. 1997

Molecular and Cellular Biology

110

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“…The possible participation of GLUTI in drug resistance was previously suggested (Vera et al, 1991). CB and PHL, two inhibitors of glucose transport, could overcome the reduced Vinca alkaloid, vinblastine, accumulation conferred by the expression of rat GLUT1 in Xenopus oocytes.…”

Section: Analysis Of Intracellular Atp Contentmentioning

confidence: 98%

“…CE has a low binding affinity for glucose transport proteins and was used as a control to demonstrate a specific glucose transporter binding by cytochalasin B (Vera et al, 1991). There was no solvent effect on cell viability or VCR uptake with dimethyl sulphoxide (DMSO) (0.08%, CB and CE).…”

Section: Glucose Transport Inhibitors and Drug Resistance 163mentioning

confidence: 99%

“…The motif AxLxxxxxxxxxxxxxG aligned to the putative CB-binding domains on GLUT1 and amino acid) was found within the mouse MRP (R Deeley, personal iication), human MRP (Cole et al, 1992), mouse GLUT1 (Kaestner et GLUT3 using Gap: (1) mouse CFTR; (2) mouse P-glycoprotein ),mouse GLUT3 (Nagamatsu et al, 1992) and mouse GLUT4 (mdrl but not mdr3); (4) Leishmania P-gpA; (5) (Rampal et al, 1980;Vera et al, 1991). hydrophilic region ( Figure 5B).…”

Section: Analysis Of Intracellular Atp Contentmentioning

confidence: 99%

“…A possible role for the glucose transporter in the modulation of multidrug resistance (MDR) was suggested (Vera et al, 1991). These investigators found that glucose transport inhibitors (GTIs) increased VCR accumulation in Xenopus oocytes transfected with GLUTI mRNA.…”

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Effect of glucose transport inhibitors on vincristine efflux in multidrug-resistant murine erythroleukaemia cells overexpressing the multidrug resistance-associated protein (MRP) and two glucose transport proteins, GLUT1 and GLUT3

Martell

Slapak²,

Levy³

1997

Br J Cancer

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SummaryThe relationship between mammalian facilitative glucose transport proteins (GLUT) and multidrug resistance was examined in two vincristine (VCR)-selected murine erythroleukaemia (MEL) PC4 cell lines. GLUT proteins, GLUT1 and GLUT3, were constitutively coexpressed in the parental cell line and also in the VCR-selected cell lines. Increased expression of the GLUT1 isoform was noted both in the PC-V40 (a non-P-glycoprotein, mrp-overexpressing subline) and in the more resistant PC-V160 (overexpressing mrp and mdr3) cell lines.Overexpression of GLUT3 was detected only in the PC-V160 subline. An increased rate of facilitative glucose transport (Vmu) and level of plasma membrane GLUT protein expression paralleled increased VCR resistance, active VCR efflux and decreased VCR steady-state accumulation in these cell lines. Glucose transport inhibitors (GTIs), cytochalasin B (CB) and phloretin blocked the active efflux and decreased steady-state accumulation of VCR in the PC-V40 subline. GTIs did not significantly affect VCR accumulation in the parental or PC-V160 cells. A comparison of protein sequences among GLUT1, GLUT3 and MRP revealed a putative cytochalasin B binding site in MRP, which displayed 44% sequence similarity/12% identity with that previously identified in GLUT1 and GLUT3; these regions also exhibited a similar hydropathy plot pattern. The findings suggested that CB bound to MRP and directly or indirectly lowered VCR efflux and/or CB bound to one or both GLUT proteins, which acted to lower the VCR efflux mediated by MRP. This is the first report of a non-neuronal murine cell line that expressed GLUT3.

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Pathophysiological and Vascular Characteristics of Solid Tumors in Relation to Drug Delivery

Vaupel

2011

Drug Delivery in Oncology

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A possible role for a mammalian facilitative hexose transporter in the development of resistance to drugs.

Abstract: We show that DI-but not L-hexoses modulate the accumulation of radioactive vinblastine in injected Xenopus laevis oocytes expressing the murine Mdrlb P-glycoprotein. We also show that X. laevis oocytes inJected with RNA encoding the rat erythroid/brain glucose transport protein (GLUT1)

Cited by 17 publications

References 68 publications

Multiple-Drug-Resistance Phenomenon in the Yeast Saccharomyces cerevisiae: Involvement of Two Hexose Transporters

Multiple-Drug-Resistance Phenomenon in the Yeast Saccharomyces cerevisiae: Involvement of Two Hexose Transporters

Effect of glucose transport inhibitors on vincristine efflux in multidrug-resistant murine erythroleukaemia cells overexpressing the multidrug resistance-associated protein (MRP) and two glucose transport proteins, GLUT1 and GLUT3

Pathophysiological and Vascular Characteristics of Solid Tumors in Relation to Drug Delivery

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