Role of cadmium in the regulation of AR gene expression and activity

Mary Beth Martin, H. James Voeller, Edward P. Gelmann, Lu Jianming, Elly Gerald Stoica, Elijah J. Hebert, Ronald Reiter, Baljit Singh, Mark Danielsen, Elizabeth Pentecost, Adriana Stoica

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

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 + 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 (GALAR) containing the hormone-binding domain of AR. The metal bound to AR with an equilibrium dissociation constant of 1.19 × 10-10 M. Cadmium blocked the binding of androgen to the receptor but did not alter its affinity (dissociation constant = 2.8 × 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.

Original languageEnglish (US)
Pages (from-to)263-275
Number of pages13
JournalEndocrinology
Volume143
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology

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