title: Role of cadmium in the regulation of AR gene expression and activity.
abstract: 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 + G(2)M 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 microg/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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Lombardi Cancer Center, E411 Research Building, 3970 Reservoir Road NW, Washington, D.C. 20007. martinmb@georgetown.edsu
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Martin
authors.forename: H James
authors.initials: HJ
authors.lastname: Voeller
authors.forename: Edward P
authors.initials: EP
authors.lastname: Gelmann
authors.forename: Jianming
authors.initials: J
authors.lastname: Lu
authors.forename: Elly-Gerald
authors.initials: EG
authors.lastname: Stoica
authors.forename: Elijah J
authors.initials: EJ
authors.lastname: Hebert
authors.forename: Ronald
authors.initials: R
authors.lastname: Reiter
authors.forename: Baljit
authors.initials: B
authors.lastname: Singh
authors.forename: Mark
authors.initials: M
authors.lastname: Danielsen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pentecost
authors.forename: Adriana
authors.initials: A
authors.lastname: Stoica
mesh_terms: D000727:Androgen-Binding Protein / Q000235:genetics; D000818:Animals; D002104:Cadmium / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D009994:Osmolar Concentration; D011467:Prostate / Q000033:anatomy & histology; D011471:Prostatic Neoplasms / Q000473:pathology; D017434:Protein Structure, Tertiary / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012669:Seminal Vesicles / Q000033:anatomy & histology; D014407:Tumor Cells, Cultured / Q000473:pathology
chemical_list: D000727:Androgen-Binding Protein; D011944:Receptors, Androgen; C027519:probasin; D002104:Cadmium