P Ruoso1, D W Hedley. 1. Division of Experimental Therapeutics, Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada.
Abstract
PURPOSE: To determine whether gamma-glutamyl transpeptidase (gamma-GT) is involved in the maintenance of elevated cysteine levels in cervical carcinoma. METHODS: Four cervical carcinoma cell lines were tested in vitro for cysteine accumulation and gamma-GT levels. The highest and lowest gamma-GT-expressing cell lines were used in in vivo experiments to determine the effect of gamma-GT inhibition on cysteine levels. RESULTS: Treatment of a series of cervical carcinoma cell lines with acivicin decreased intracellular cysteine concentrations. Cysteine depletion was evident in Me180 cells which had the greatest levels of gamma-GT activity, and had a more pronounced cysteine decrease in medium with glutathione and cysteine concentrations simulating the in vivo situation. Also investigated were the effects of inhibition of gamma-GT activity on intracellular cysteine levels in xenografts grown in severe combined immunodeficient (SCID) mice. With the use of 35 mg/kg of acivicin, gamma-GT activity decreased to basal levels of detection in both tumour types and significant decreases in cysteine levels were seen in the high gamma-GT-expressing tumours (Me180). Thus, inhibition of gamma-GT activity may have therapeutic potential in high-expressing cancers. CONCLUSIONS: In tumours and cell lines with elevated levels of gamma-GT activity, inhibition of this enzyme led to decreases of cysteine levels.
PURPOSE: To determine whether gamma-glutamyl transpeptidase (gamma-GT) is involved in the maintenance of elevated cysteine levels in cervical carcinoma. METHODS: Four cervical carcinoma cell lines were tested in vitro for cysteine accumulation and gamma-GT levels. The highest and lowest gamma-GT-expressing cell lines were used in in vivo experiments to determine the effect of gamma-GT inhibition on cysteine levels. RESULTS: Treatment of a series of cervical carcinoma cell lines with acivicin decreased intracellular cysteine concentrations. Cysteine depletion was evident in Me180 cells which had the greatest levels of gamma-GT activity, and had a more pronounced cysteine decrease in medium with glutathione and cysteine concentrations simulating the in vivo situation. Also investigated were the effects of inhibition of gamma-GT activity on intracellular cysteine levels in xenografts grown in severe combined immunodeficient (SCID) mice. With the use of 35 mg/kg of acivicin, gamma-GT activity decreased to basal levels of detection in both tumour types and significant decreases in cysteine levels were seen in the high gamma-GT-expressing tumours (Me180). Thus, inhibition of gamma-GT activity may have therapeutic potential in high-expressing cancers. CONCLUSIONS: In tumours and cell lines with elevated levels of gamma-GT activity, inhibition of this enzyme led to decreases of cysteine levels.
Authors: Ankita Bansal; Danielle J Sanchez; Vivek Nimgaonkar; David Sanchez; Romain Riscal; Nicolas Skuli; M Celeste Simon Journal: Mol Cancer Res Date: 2019-05-31 Impact factor: 5.852
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