Overexpression of the multidrug resistance‐associated protein (MRP1) in human heavy metal‐selected tumor cells

FEBS Letters

Guillouzo, André¹  Vernhet, Laurent¹  Allain, Nathalie¹  Anger, Jean-Pierre¹  Courtois, Arnaud¹  Fardel, Olivier¹  Payen, Léa¹ 

[1] INSERM U456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, 2 avenue Léon Bernard, 35043 Rennes Cedex, France

关键词: Multidrug resistance-associated protein;    Heavy metal;    Drug resistance;    Membrane transport;    Antimony;    MT;    metallothioneins;    ABC;    ATP-binding cassette;    P-gp;    P-glycoprotein;    MRP1;    multidrug resistance-associated protein 1;    cMOAT;    canalicular multispecific organic anion transporter;    YCF1;    yeast cadmium resistance factor 1;    Sb(III);    potassium antimony tartrate;    RT-PCR;    reverse transcriptase-polymerase chain reaction;    MTT;    3-(4;    5-dimethylthiazol-2-yl)-2;    5-diphenyltetrazolium bromide;   

DOI  :  10.1016/S0014-5793(98)01716-5

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown