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Overexpression of the multidrug resistance‐associated protein (MRP1) in human heavy metal‐selected tumor cells
Author(s) -
Vernhet Laurent,
Courtois Arnaud,
Allain Nathalie,
Payen Léa,
Anger Jean-Pierre,
Guillouzo André,
Fardel Olivier
Publication year - 1999
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(98)01716-5
Subject(s) - multiple drug resistance , metal , chemistry , cancer research , microbiology and biotechnology , biology , biochemistry , antibiotics , organic chemistry
Cellular and molecular mechanisms involved in the resistance to cytotoxic heavy metals remain largely to be characterized in mammalian cells. To this end, we have analyzed a metal‐resistant variant of the human lung cancer GLC4 cell line that we have selected by a step‐wise procedure in potassium antimony tartrate. Antimony‐selected cells, termed GLC4/Sb30 cells, poorly accumulated antimony through an enhanced cellular efflux of metal, thus suggesting up‐regulation of a membrane export system in these cells. Indeed, GLC4/Sb30 cells were found to display a functional overexpression of the multidrug resistance‐associated protein MRP1, a drug export pump, as demonstrated by Western blotting, reverse transcriptase‐polymerase chain reaction and calcein accumulation assays. Moreover, MK571, a potent inhibitor of MRP1 activity, was found to markedly down‐modulate resistance of GLC4/Sb30 cells to antimony and to decrease cellular export of the metal. Taken together, our data support the conclusion that overexpression of functional MRP1 likely represents one major mechanism by which human cells can escape the cytotoxic effects of heavy metals.