PMID- 10399958
OWN - NLM
STAT- MEDLINE
DCOM- 19990727
LR  - 20190708
IS  - 0020-7136 (Print)
IS  - 0020-7136 (Linking)
VI  - 82
IP  - 3
DP  - 1999 Jul 30
TI  - Co-expression of gamma-glutamylcysteine synthetase sub-units in response to 
      cisplatin and doxorubicin in human cancer cells.
PG  - 405-11
AB  - Glutathione (gamma-glutamylcysteinyl glycine, GSH) is believed to be important in 
      the acquisition of resistance to anti-cancer drugs such as cisplatin (CDDP) and 
      doxorubicin (DOX). gamma-Glutamylcysteine synthetase (gamma-GCS) is a key enzyme 
      for maintaining intracellular GSH levels; it is composed of a catalytic heavy 
      (gamma-GCSh) and a regulatory light (gamma-GCSl) sub-unit. In the present study, 
      the expression of gamma-GCS sub-units was examined in human cancer cell lines. 
      The levels of GSH, the expression of gamma-GCSh and gamma-GCSl mRNAs and proteins 
      in human cancer cells were higher in CDDP-resistant cells and DOX-resistant cells 
      than in the drug-sensitive cells. Treatment of CDDP/DOX-resistant human 
      colonic-cancer cells (HCT8DDP) with CDDP and DOX caused simultaneous induction of 
      the expression of gamma-GCSh and gamma-GCSl mRNAs. The transcriptional regulation 
      of gamma-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 gamma-GCSh-promoter gene and the coding region for luciferase. The HCT8DDP 
      cells transiently transfected with a plasmid containing an AP-1 site of the 
      gamma-GCSh-promoter-luciferase construct showed increased luciferase activity 
      when treated with CDDP and DOX. These results suggest that stimulation of the 
      expression of gamma-GCSh by CDDP and DOX is mediated by AP-1, which relates to 
      the resistance of cancer cells to the drug.
FAU - Iida, T
AU  - Iida T
AD  - Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease 
      Institute, Nagasaki University School of Medicine, Nagasaki City, Japan.
FAU - Mori, E
AU  - Mori E
FAU - Mori, K
AU  - Mori K
FAU - Goto, S
AU  - Goto S
FAU - Urata, Y
AU  - Urata Y
FAU - Oka, M
AU  - Oka M
FAU - Kohno, S
AU  - Kohno S
FAU - Kondo, T
AU  - Kondo T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Peptide Fragments)
RN  - 0 (Transcription Factor AP-1)
RN  - 80168379AG (Doxorubicin)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 6.3.2.2 (Glutamate-Cysteine Ligase)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Cisplatin/administration & dosage
MH  - Doxorubicin/administration & dosage
MH  - Enzyme Induction
MH  - Glutamate-Cysteine Ligase/*biosynthesis/chemistry
MH  - Humans
MH  - Luciferases/metabolism
MH  - Peptide Fragments/*biosynthesis
MH  - Promoter Regions, Genetic
MH  - Transcription Factor AP-1/physiology
MH  - Tumor Cells, Cultured
EDAT- 1999/07/10 10:00
MHDA- 2000/06/20 09:00
CRDT- 1999/07/10 10:00
PHST- 1999/07/10 10:00 [pubmed]
PHST- 2000/06/20 09:00 [medline]
PHST- 1999/07/10 10:00 [entrez]
AID - 10.1002/(SICI)1097-0215(19990730)82:3<405::AID-IJC14>3.0.CO;2-M [pii]
AID - 10.1002/(sici)1097-0215(19990730)82:3<405::aid-ijc14>3.0.co;2-m [doi]
PST - ppublish
SO  - Int J Cancer. 1999 Jul 30;82(3):405-11. doi: 
      10.1002/(sici)1097-0215(19990730)82:3<405::aid-ijc14>3.0.co;2-m.