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Alteration in -Glutamyl Transpeptidase Activity and Messenger RNA of Human Prostate Carcinoma Cells by Androgen¹

University of Wisconsin Comprehensive Cancer Center, Department of Medicine, Environmental Toxicology Center [M. O. R., G. W.], and the William S. Middleton Veterans Administration Hospital [P. A. P.], University of Wisconsin, Madison, Wisconsin 53792

Concentrations of the synthetic androgen R1881 that correspond to physiologically relevant concentrations of 5-dihydrotestosterone are capable of altering the activity of -glutamyl transpeptidase (GGT) in human prostate carcinoma cells. GGT activity of the androgen-responsive prostate cancer cell line LNCaP increases >50% above that of the control after a 72-h exposure to 1 nM R1881. This elevation in GGT activity occurs as early as 48 h after treatment and is maintained for at least 96 h. Loss of glutathione (GSH) from media and accumulation of intracellular GSH of cells pretreated with 1 nM R1881 occur at a higher rate than in control cells, suggesting that a greater rate of GSH salvage is associated with the increased GGT activity. Immunohistochemical staining detects an increase in GGT-positive staining in cells treated with 1 nM R1881 for 72 h. Steady-state mRNA levels for GGT are elevated above those of the control 24–72 h after treatment. R1881 has no effect on the GGT activity of the androgen-independent prostate cell line DU145. Growth of LNCaP but not DU145 cells is inhibited by 1 nM R1881 compared to that of the control. Inhibitors of GGT activity, acivicin and serine-borate, are capable of dampening or blocking the effect of R1881 on growth. Growth of LNCaP cells treated with 1 nM R1881 plus 100 mM glycylglycine, a stimulator of GGT activity, is inhibited to a greater extent than the growth of LNCaP cells treated with R1881 alone. These data demonstrate that androgens can elevate GGT activity and increase GGT mRNA and protein levels in human prostate carcinoma cells. In addition, compounds able to alter GGT activity are capable of altering androgen-related growth effects.

¹ Supported by Veterans Administration, Environmental Toxicology Training Grant 5-T32-ES07015-18. Cap CURE.

² To whom requests for reprints should be addressed, at Medical Oncology Section, Department of Medicine, University of Wisconsin, K6/550 CSC, 600 Highland Avenue, Madison, WI 53792. Phone: (608) 265-8131.

Received 11/18/96. Accepted 4/22/97.

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