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Co-expression of gamma-glutamylcysteine synthetase sub-units in response to cisplatin and doxorubicin in human cancer cells

โœ Scribed by Tetsuya Iida; Eri Mori; Katsuharu Mori; Shinji Goto; Yoshishige Urata; Mikio Oka; Shigeru Kohno; Takahito Kondo

Publisher
John Wiley and Sons
Year
1999
Tongue
French
Weight
178 KB
Volume
82
Category
Article
ISSN
0020-7136

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โœฆ Synopsis

Glutathione (โฅ-glutamylcysteinyl glycine, GSH) is believed to be important in the acquisition of resistance to anti-cancer drugs such as cisplatin (CDDP) and doxorubicin (DOX). โฅ-Glutamylcysteine synthetase (โฅ-GCS) is a key enzyme for maintaining intracellular GSH levels; it is composed of a catalytic heavy (โฅ-GCSh) and a regulatory light (โฅ-GCSl) sub-unit. In the present study, the expression of โฅ-GCS sub-units was examined in human cancer cell lines. The levels of GSH, the expression of โฅ-GCSh and โฅ-GCSl mRNAs and proteins in human cancer cells were higher in CDDPresistant cells and DOX-resistant cells than in the drugsensitive cells. Treatment of CDDP/DOX-resistant human colonic-cancer cells (HCT8DDP) with CDDP and DOX caused simultaneous induction of the expression of โฅ-GCSh and โฅ-GCSl mRNAs. The transcriptional regulation of โฅ-GCS was studied and it was observed that the DNA-binding activity of activator protein 1 (AP-1) is induced by CDDP and DOX using an electrophoretic mobility shift assay. We constructed chimeric genes containing various regions of the โฅ-GCShpromoter gene and the coding region for luciferase. The HCT8DDP cells transiently transfected with a plasmid containing an AP-1 site of the โฅ-GCSh-promoter-luciferase construct showed increased luciferase activity when treated with CDDP and DOX. These results suggest that stimulation of the expression of โฅ-GCSh by CDDP and DOX is mediated by AP-1, which relates to the resistance of cancer cells to the drug.

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