Gamma-glutamylcysteine synthetase gene overexpression results in increased activity of the ATP-dependent glutathione S-conjugate export pump and cisplatin resistance.
The ATP-dependent glutathione S-conjugate export pump (GS-X pump) has been suggested to play a role in the mechanism of cisplatin resistance. The purpose of this study was to determine the relationship between intracellular glutathione (GSH) levels and GS-X pump activity and whether GS-X pump overexpression results in cisplatin resistance. We transfected the human gamma-glutamylcysteine synthetase (gamma-GCS) gene into a human small-cell lung cancer cell line, SBC-3, producing SBC-3/GCS. The intracellular GSH content of SBC-3/GCS was twice that of the parental line, its GS-X pump activity was significantly enhanced and cellular cisplatin accumulation decreased. SBC-3/GCS showed higher resistance (relative resistance value of 7.4) to cisplatin than the parental line SBC-3. These data indicate that gamma-GCS gene overexpression induces cellular cisplatin resistance associated with increases in both the GSH content and GS-X pump activity, resulting in reduced cisplatin accumulation. In conclusion, GS-X pump expression is related to cellular GSH metabolism and involved in cisplatin resistance.
D000255:Adenosine Triphosphate / Q000378:metabolism; D001483:Base Sequence; D018288:Carcinoma, Small Cell; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002945:Cisplatin / Q000378:metabolism / Q000633:toxicity*; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D015723:Gene Library; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D017997:Leukotriene C4 / Q000378:metabolism; D008175:Lung Neoplasms; D026901:Membrane Transport Proteins; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000096:biosynthesis; D013950:Thymus Gland / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D011994:Recombinant Proteins; C086860:glutathione transporter; D017997:Leukotriene C4; D000255:Adenosine Triphosphate; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D002945:Cisplatin