Androgen enhances the antiproliferative activity of Vitamin D 3 by suppressing 24-hydroxylase expression in LNCaP cells

Abstract

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 1α,25-dihydroxyvitamin D 3. In this paper, we demonstrate that 25-hydroxyvitamin D 3 at 500 nM significantly increases the expression of 24-hydroxylase mRNA and the increase is significantly decreased by 5α-dihydrotestosterone (DHT) at concentrations of 1–100 nM in androgen-sensitive prostate cancer cells LNCaP. 25-Hydroxyvitamin D 3 at 500 nM and 1α,25-dihydroxyvitamin D 3 at 10 nM inhibit LNCaP cell growth, and the growth inhibition is enhanced by 1 nM DHT. Neither 25-hydroxyvitamin D 3 nor 1α,25-dihydroxyvitamin D 3 at physiological concentrations has growth effect. However, in the presence of 1 nM DHT, both 25-hydroxyvitamin D 3 and 1α,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 1α,25-dihydroxyvitamin D 3, the present results demonstrate, for the first time, that both 25-hydroxyvitamin D 3 and 1α,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.