Role of cadmium in the regulation of AR gene expression and activity.
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.
Martin
Mary Beth
MB
Department of Biochemistry and Molecular Biology, Lombardi Cancer Center, E411 Research Building, 3970 Reservoir Road NW, Washington, D.C. 20007. martinmb@georgetown.edsu
Voeller
H James
HJ
Gelmann
Edward P
EP
Lu
Jianming
J
Stoica
Elly-Gerald
EG
Hebert
Elijah J
EJ
Reiter
Ronald
R
Singh
Baljit
B
Danielsen
Mark
M
Pentecost
Elizabeth
E
Stoica
Adriana
A
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
D000727:Androgen-Binding Protein; D011944:Receptors, Androgen; C027519:probasin; D002104:Cadmium