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Multidrug Resistance-associated Protein-1 (MRP-1)-dependent Glutathione Disulfide (GSSG) Efflux as a Critical Survival Factor for Oxidant-enriched Tumorigenic Endothelial Cells.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2016 May 06; Vol. 291 (19), pp. 10089-103. Date of Electronic Publication: 2016 Mar 09. - Publication Year :
- 2016
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Abstract
- Endothelial cell tumors are the most common soft tissue tumors in infants. Tumor-forming endothelial (EOMA) cells are able to escape cell death fate despite excessive nuclear oxidant burden. Our previous work recognized perinuclear Nox-4 as a key contributor to EOMA growth. The objective of this work was to characterize the mechanisms by which EOMA cells evade oxidant toxicity and thrive. In EOMA cells, compared with in the cytosol, the nuclear GSSG/GSH ratio was 5-fold higher. Compared to the ratio observed in healthy murine aortic endothelial (MAE) cells, GSSG/GSH was over twice as high in EOMA cells. Multidrug resistance-associated protein-1 (MRP-1), an active GSSG efflux mechanism, showed 2-fold increased activity in EOMA compared with MAE cells. Hyperactive YB-1 and Ape/Ref-1 were responsible for high MRP-1 expression in EOMA. Proximity ligand assay demonstrated MRP-1 and YB-1 binding. Such binding enabled the nuclear targeting of MRP-1 in EOMA in a leptomycin-B-sensitive manner. MRP-1 inhibition as well as knockdown trapped nuclear GSSG, causing cell death of EOMA. Disulfide loading of cells by inhibition of GSSG reductase (bischoloronitrosourea) or thioredoxin reductase (auranofin) was effective in causing EOMA death as well. In sum, EOMA cells survive a heavy oxidant burden by rapid efflux of GSSG, which is lethal if trapped within the cell. A hyperactive MRP-1 system for GSSG efflux acts as a critical survival factor for these cells, making it a potential target for EOMA therapeutics.<br /> (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Animals
Auranofin pharmacology
Cell Line, Tumor
Cell Survival drug effects
Cell Survival genetics
DNA-(Apurinic or Apyrimidinic Site) Lyase genetics
DNA-(Apurinic or Apyrimidinic Site) Lyase metabolism
Endothelial Cells pathology
Fatty Acids, Unsaturated pharmacology
Gene Expression Regulation, Neoplastic drug effects
Glutathione Disulfide genetics
Mice
Multidrug Resistance-Associated Proteins genetics
Neoplasm Proteins genetics
Transcription Factors genetics
Transcription Factors metabolism
Vascular Neoplasms drug therapy
Vascular Neoplasms genetics
Vascular Neoplasms pathology
Endothelial Cells metabolism
Glutathione Disulfide metabolism
Multidrug Resistance-Associated Proteins metabolism
Neoplasm Proteins metabolism
Vascular Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 291
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26961872
- Full Text :
- https://doi.org/10.1074/jbc.M115.688879