Document Detail

Coordinate changes in expression of protective genes in drug-resistant cells.
MedLine Citation:
PMID:  9679555     Owner:  NLM     Status:  MEDLINE    
Maintenance of cellular homeostasis is a critical survival trait when cells are exposed to electrophilic chemicals. Because conjugation and elimination of these toxins is dependent upon sequential and coordinated metabolic pathways, acquired resistance through a gradual adaptive response would rarely be expected to be the consequence of changes in one gene product. Human HT29 colon cancer cells chronically exposed to EA have acquired resistance to the drug. Commensurate with resistance, EA is more effectively conjugated to GSH and effluxed from the resistant cells. Using directed and random (differential display) approaches, a number of detoxification and/or protective gene products have been shown to be expressed at elevated levels. These include gamma-GCS (approximately 3-fold), GST-pi (approximately 3-fold), MRP (approximately 3-fold), NQO1 (approximately 3-fold), DDH (20-fold), and SSP 3521, a transcriptional regulator (approximately 3-fold). Multiple mechanisms contribute to these increases, including enhanced transcriptional rate and prolonged mRNA and protein half lives. Further indications for the involvement of transcriptional regulators is found in HL60 adriamycin-resistant cells which overexpress MRP, GST-pi and gamma-GCS and also have 15-20-fold more DNA-dependent protein kinase. It is possible that this enzyme serves as an early stress response gene which may activate downstream transcription factors. Intriguingly, the catalytic subunit of DNA-dependent protein kinase has a high avidity for [35S]azidophenacyl-GSH. High levels of GSH conjugates indicate cell stress and it would seem reasonable to speculate that DNA-dependent protein kinase may serve as a receiver and transmitter of signals which contribute to drug resistance and maintain cell viability.
K D Tew; M O'Brien; N M Laing; H Shen
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Chemico-biological interactions     Volume:  111-112     ISSN:  0009-2797     ISO Abbreviation:  Chem. Biol. Interact.     Publication Date:  1998 Apr 
Date Detail:
Created Date:  1998-08-10     Completed Date:  1998-08-10     Revised Date:  2012-06-25    
Medline Journal Info:
Nlm Unique ID:  0227276     Medline TA:  Chem Biol Interact     Country:  IRELAND    
Other Details:
Languages:  eng     Pagination:  199-211     Citation Subset:  IM    
Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
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MeSH Terms
Alcohol Oxidoreductases / genetics,  metabolism
Antineoplastic Agents / pharmacology
DNA-Activated Protein Kinase
DNA-Binding Proteins*
Doxorubicin / metabolism,  pharmacology
Drug Resistance / genetics*,  physiology
Ethacrynic Acid / metabolism,  pharmacology
Gene Expression*
Glutamate-Cysteine Ligase / genetics,  metabolism
Glutathione / metabolism
Glutathione Transferase / genetics,  metabolism
Nuclear Proteins
Oxidoreductases Acting on CH-CH Group Donors*
Protein-Serine-Threonine Kinases / genetics,  metabolism
Tumor Cells, Cultured
Reg. No./Substance:
0/Antineoplastic Agents; 0/DNA-Binding Proteins; 0/Nuclear Proteins; 23214-92-8/Doxorubicin; 58-54-8/Ethacrynic Acid; 70-18-8/Glutathione; EC 1.-/Oxidoreductases; EC 1.1.-/Alcohol Oxidoreductases; EC 1.1.-/dihydrodiol dehydrogenases; EC 1.3.-/Oxidoreductases Acting on CH-CH Group Donors; EC,2-dihydro-1,2-dihydroxynaphthalene dehydrogenase; EC Transferase; EC Protein Kinase; EC protein, human; EC Kinases; EC Ligase

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