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© 1995 Oxford University Press
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Expression of gamma-glutamyl transpeptidase provides tumor cells with a selective growth advantage at physiologic concentrations of cyst(e)ine
Department of Cell Biology and Department of Obstetrics and Gynecology, University of Virginia Health Sciences Center Charlottesville, Virginia 22908, USA
Cells from the GGT-negative mouse hepatoma cell line, Hepa 16, were transfected with a human GGT cDNA and stably transformed clones were isolated. In standard tissue culture medium the GGT-positive cells and GGT-negative controls grew equally well. However, when the cysteine concentration of the medium was reduced to physiologic levels the GGT-positive cells had a growth advantage. Further investigation revealed that the medium of the GGT-negative Hepa 16 cells contained glutathione that had been excreted by the cells, but no glutathione was present in the medium of the GGT-positive cells. We have previously shown that expression of GGT enables cells to use extracellular glutathione as a source of cysteine (Hanigan and Ricketts, Biochem., 32:6302, 1993). These new data reveal that physiologic levels of cysteine can be limiting for cell growth and expression of GGT can provide the cells with a selective growth advantage. These data explain the observation that cells transfected with GGT grow at the same rate as the GGT-negative controls in tissue culture medium which contains a high level of cysteine, but the GGT-positive cells grow more rapidly than the GGT-negative cells when transplanted into animals (Warren et al., Proc. Soc. Exp. Biol. Med., 202:9, 1993). GGT-positive tumor cells have a selective growth advantage in vivo in comparison to GGT-negative tumor cells because they are able to use serum glutathione as a secondary source of cysteine thereby overcoming the growth restriction imposed by serum levels of cysteine.
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