Androgen enhances the antiproliferative activity of Vitamin D3 by suppressing 24-hydroxylase expression in LNCaP cells

25-Hydroxyvitamin D-3-24-hydroxylase (24-hydroxylase, CYP24) is an important inactivating enzyme controlling the concentrations of both active metabolites 25-hydroxyvitamin D-3 and 1 alpha,25-dihydroxyvitamin D-3. In this paper, we demonstrate that 25-hydroxyvitamin D3 at 500 nM significantly increases the expression of 24-hydroxylase mRNA and the increase is significantly decreased by 5 alpha-dihydrotestosterone (DHT) at concentrations of 1-100 nM in androgen-sensitive prostate cancer cells LNCaP. 25-Hydroxyvitamin D-3 at 500 nM and 1 alpha,25-dihydroxyvitamin D-3 at 10nM inhibit LNCaP bell growth, and the growth inhibition is enhanced by I nM DHT. Neither 25-hydroxyvitamin D-3 nor 1 alpha,25-dihydroxyvitamin D-3 at physiological concentrations has growth effect. However, in the presence of I nM DHT, both 25-hydroxyvitamin D-3 and 1 alpha,25-dihydroxyvitamin D-3 at physiological concentrations are clearly antiproliferative. These data demonstrate that DHT enhances the antiproliferative activity of Vitamin D-3 hormones by inhibiting their inactivating enzyme. Most previous studies on Vitamin D-3 action in cell cultures have used pharmacological concentrations of 1 alpha,25-dihydroxyvitamin D-3, the present results demonstrate, for the first time, that both 25-hydroxyvitamin D-3 and 1 alpha,25-dihydroxyvitamin D-3 at physiological concentrations are active in the presence of physiological concentration of androgen. The combined use of androgen and Vitamin D-3 metabolites could be a promising treatment for prostate cancer. (c) 2006 Elsevier Ltd. All rights reserved.