Androgen enhances the antiproliferative activity of vitamin D3 by suppressing 24-hydroxylase expression in LNCaP cells.
25-Hydroxyvitamin D3-24-hydroxylase (24-hydroxylase, CYP24) is an important inactivating enzyme controlling the concentrations of both active metabolites 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3. 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 5alpha-dihydrotestosterone (DHT) at concentrations of 1-100 nM in androgen-sensitive prostate cancer cells LNCaP. 25-Hydroxyvitamin D3 at 500 nM and 1alpha,25-dihydroxyvitamin D3 at 10 nM inhibit LNCaP cell growth, and the growth inhibition is enhanced by 1 nM DHT. Neither 25-hydroxyvitamin D3 nor 1alpha,25-dihydroxyvitamin D3 at physiological concentrations has growth effect. However, in the presence of 1 nM DHT, both 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3 at physiological concentrations are clearly antiproliferative. These data demonstrate that DHT enhances the antiproliferative activity of Vitamin D3 hormones by inhibiting their inactivating enzyme. Most previous studies on Vitamin D3 action in cell cultures have used pharmacological concentrations of 1alpha,25-dihydroxyvitamin D3, the present results demonstrate, for the first time, that both 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3 at physiological concentrations are active in the presence of physiological concentration of androgen. The combined use of androgen and Vitamin D3 metabolites could be a promising treatment for prostate cancer.
Lou
Yan-Ru
YR
Department of Anatomy, Medical School, University of Tampere, and Department of Clinical Chemistry, Tampere University Hospital, FIN-33014, Finland. loyalo@uta.fi
Tuohimaa
Pentti
P
D000728:Androgens / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D008297:Male; D011467:Prostate / Q000201:enzymology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase
D000728:Androgens; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D002762:Cholecalciferol; D013250:Steroid Hydroxylases; C406322:vitamin D 1-alpha hydroxylase; D065668:Vitamin D3 24-Hydroxylase