L. Vernhet et al., Overexpression of the multidrug resistance-associated protein (MRP1) in human heavy metal-selected tumor cells, FEBS LETTER, 443(3), 1999, pp. 321-325
Cellular and molecular mechanisms involved in the resistance to cytotoxic h
eavy metals remain largely to be characterized in mammalian cells. To this
end, we have analyzed a metal-resistant variant of the human lung cancer GL
C4 cell line that we have selected by a step-wise procedure in potassium an
timony tartrate. Antimony-selected cells, termed GLC4/Sb30 cells, poorly ac
cumulated antimony through an enhanced cellular efflux of metal, thus sugge
sting up-regulation of a membrane export system in these cells. Indeed, GLC
4/Sb30 cells were found to display a functional overexpression of the multi
drug resistance-associated protein MRP1, a drug export pump, as demonstrate
d by Western blotting, reverse transcriptase-polymerase chain reaction and
calcein accumulation assays, Moreover, MK571, a potent inhibitor of MRP1 ac
tivity, was found to markedly down-modulate resistance of GLC4/Sb30 cells t
o antimony and to decrease cellular export of the metal. Taken together, ou
r data support the conclusion that overexpression of functional MRP1 likely
represents one major mechanism by which human cells can escape the cytotox
ic effects of heavy metals. (C) 1999 Federation of European Biochemical Soc
ieties.