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Mrp-1 Dependent Gssg Efflux As A Critical Survival Factor For Oxidant Enriched Tumor Forming Endothelial Cells
Gayle M. Gordillo, MD, Ayan Biswas, PhD, Savita Khanna, PhD, Xueliang Pan, PhD, Chandan K. Sen, PhD.
The Ohio State University, Columbus, OH, USA.

PURPOSE: Highly elevated levels of Nox-4, a protein that
generates H2O2, is seen in both human hemangiomas and a
murine model of hemangioendothelioma. Tumor-forming endothelial (EOMA) cells are able to escape cell death despite excessive Nox-4 derived nuclear oxidantburden. The objective of this work was to characterize the mechanisms by which EOMA cells evade oxidant toxicity and thrive.
METHODS: Multidrug resistance-associated protein-1 (MRP-1) is
a transport protein that eliminates toxic molecules from cells including
chemotherapy agents such as vinca alkaloids and oxidized glutathione (GSSG). MRP-1 activity was measured by calcein exclusion and glutathione measurements madeusing high performance liquid chromatography.
RESULTS: In EOMA nuclear GSSG/GSH ratio was five-fold higher
compared to cytosol. Compared to those in healthy murine arterial endothelial cells (MAE), cellular GSSG/GSH was over twice in EOMA. MRP-1 activity was twice as high in EOMA compared to MAE. Hyperactive YB-1 and Ape/Ref-1 wereresponsible for high MRP-1 inhibition and knockdown resulted in elevation of nuclear GSSG causing death of EOMA cells. Disulfide loading of cells by inhibition of GSSG reductase was effective in causing EOMA death as well. In sum, EOMA cells survive a heavy oxidant burden by rapid efflux of GSSG, whichis lethal if trapped within the cell.
CONCLUSION: A hyperactive MRP-1 system for GSSG efflux acts as a
critical survival factor for these cells, but it also promotes chemotherapy
resistance. MRP-1 may be a productive target for endothelial cell tumor
therapeutics.


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