Artikel
Multidrug resistance proteins (MRPs) in human brain and gliomas
Multidrug resistance-Proteine (MRPs) im Gehirn des Menschen und in Gliomen
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Autoren
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A. Nies
- Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg
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H. Bronger
- Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg
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J. König
- Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg
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H. H. Steiner
- Molecular Biology Laboratory, Neurosurgery Hospital, University of Heidelberg
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C. Herold-Mende
- Molecular Biology Laboratory, Neurosurgery Hospital, University of Heidelberg
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H. P. Schmitt
- Department of Neuropathology, Institute of Pathology, University of Heidelberg
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D. Keppler
- Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg
| Veröffentlicht: | 4. Mai 2005 |
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Gliederung
Text
Objective
Gliomas regularly show a high degree of resistance against chemotherapeutic drugs. The export of chemotherapeutic drugs by ATP-dependent transporters localized in the plasma membrane of malignant cells is an important molecular mechanism by which malignant cells may acquire a multidrug resistant phenotype. Multidrug resistance proteins (MRPs) of the ABCC subfamily mediate the ATP-dependent export of organic anions, including cytotoxic and antiviral drugs, from cells. The objective of the study was to identify MRP family members possibly involved in the intrinsic resistance of human brain to cytotoxic and antiviral drugs.
Methods
We analyzed expression and localization of MRP1-MRP6 in rapidly frozen perilesional samples of several regions of adult human brain and in 60 glioma samples of different WHO grades obtained during neurosurgery. Quantitative PCR and immunofluorescence microscopy were performed to identify MRP isoforms in human brain and gliomas.
Results
In perilesional tissue samples, quantitative PCR indicated expression of MRP1, MRP4, and MRP5 mRNA, low amounts of MRP2 and MRP3 mRNA, whereas MRP6 mRNA was below detectability. However, immunofluorescence microscopy of cryosections from human brain showed no reactivity for the MRP2 or MRP3 proteins. MRP1, MRP4, and MRP5 were localized by confocal laser scanning microscopy to the luminal side of brain capillary endothelial cells. The MRP4 and MRP5 proteins were also detected in astrocytes of the subcortical white matter. In addition, MRP5 protein was present in pyramidal neurons. Immunofluorescence analysis of 60 glioma samples showed that MRP4 and MRP5 are the major isoforms expressed in human gliomas. MRP4 and MRP5 were localized in the luminal membrane of capillary endothelial cells in 52/60 and 54/60 glioma samples, respectively. In addition, both MRP isoforms were present in the glioma cells. Semi-quantitative immunofluorescence analysis indicated that expression of MRP4 and MRP5 in the glioma cells correlated with tumor histology rather than with tumor grade.
Conclusions
MRP proteins may contribute to the cellular efflux of endogenous anionic glutathione or glucuronate conjugates (substrates for MRP1), cyclic nucleotides (substrates for MRP4 and MRP5), glutathione (co-substrate for MRP1 and MRP4), as well as of cytotoxic drugs.
