The effect of inhibition of glutathione S-transferase P on the growth of the Jurkat human T cell line.
To investigate the possible role of glutathione S-transferase P (GSTP) in carcinogenesis and cell proliferation, ethacrynic acid (EA) was used to inhibit GSTP in the human Jurkat T cell line. At lower doses (0-30 microM), EA led to a decreased rate of proliferation as assessed by the MTT assay. This was associated with a decreased DNA S+G2/M phase population and also a dose-dependent increase in apoptosis. At concentrations of EA > 30 microM, cells suffered non-specific cytotoxic injury and underwent necrosis. The total cell number fell over the time course of the experiment. A resistant subculture of cells which proliferated in the presence of EA at 30 microM was selected by continuous growth in the presence of EA. Although this had a higher basal rate of apoptosis than control cells, it also showed a significantly larger growth fraction as assessed by flow cytometry. GSTP is frequently overexpressed in human tumours and animal models of carcinogenesis, and is regarded as a marker of the 'drug-resistant phenotype' of initiated cells. Our findings suggest that the role of GSTP in models of chemical carcinogenesis and in tumours may be its permissive effect on cell cycle activity and downregulation of apoptosis, thus allowing expansion of a population of initiated cells.
McCaughan
F M
FM
University Department of Pathology, University of Edinburgh, U.K.
Brown
A L
AL
Harrison
D J
DJ
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004976:Ethacrynic Acid / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D016399:Lymphoma, T-Cell / Q000201:enzymology* / Q000473:pathology; D014407:Tumor Cells, Cultured
D005982:Glutathione Transferase; D004976:Ethacrynic Acid