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Role of Cadmium in the Regulation of AR Gene Expression and Activity

Departments of Biochemistry and Molecular Biology (M.B.M., J.L., M.D., E.P., A.S.) and Oncology (M.B.M., H.J.V., E.P.G., E.-G.S., E.J.H., R.R., B.S., A.S.), Lombardi Cancer Center, School of Nursing and Health Studies (A.S.), Georgetown University, Washington, D.C. 20007

Address all correspondence and requests for reprints to: Mary Beth Martin, Lombardi Cancer Center, E411 Research Building, 3970 Reservoir Road NW, Washington, D.C. 20007. E-mail: martinmb{at}georgetown.edu

Treatment of human prostate cancer cells, LNCaP, with cadmium stimulated cell growth. There was a 2.4-fold increase in the population of cells in the S + G₂M phase by d 4 and a 2.7-fold increase in cell number by d 8. The metal decreased the concentration of AR protein and mRNA (80 and 60%, respectively) and increased the expression of prostate-specific antigen and the homeobox gene, NKX 3.1 (6-fold) that was blocked by an antiandrogen. In addition, cadmium activated the AR in mouse L cells containing an MMTV-luciferase reporter gene (4-fold increase) and in COS-1 cells transfected with wild-type AR and an MMTV-CAT reporter gene (7-fold increase). Cadmium also activated a chimeric receptor (GAL-AR) containing the hormone-binding domain of AR. The metal bound to AR with an equilibrium dissociation constant of 1.19 x 10^-10 M. Cadmium blocked the binding of androgen to the receptor but did not alter its affinity (dissociation constant = 2.8 x 10^-10 M), suggesting that the metal is an inhibitor of hormone binding. In castrated animals, a single, low, environmentally relevant dose of cadmium (20 µg/kg body weight) increased the wet weight of the prostate (1.97- to 3-fold) and the seminal vesicle complex (approximately 1.5-fold) and increased the expression of the androgen-regulated gene, probasin (27-fold). The in vivo effects were also blocked by an antiandrogen.

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