Vitamin D receptor expression is required for growth modulation by 1 alpha,25-dihydroxyvitamin D-3 in the human prostatic carcinoma cell line ALVA-31

Epidemiological data suggest that vitamin D-3, obtained from dietary sources and sunlight exposure, protects against mortality from prostate cancer (PC). In agreement with this, the most active vitamin D metabolite 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2) D-3] regulates the growth and differentiation of several human PC cell lines. Both genomic and non-genomic signalling pathways for 1,25(OH)(2) D-3 have been reported, although the mechanism of action in PC cells has not been defined. We now provide data supporting an active role for the nuclear vitamin D receptor (VDR) in mediating the growth-inhibitory effects of 1,25(OH)(2) D-3 on these cells. In the VDR-rich cell line ALVA-31, the observed changes in growth by 1,25(OH)(2) D-3 are preceded by significant changes in VDR mRNA expression. In contrast, the cell line JCA-1, containing few VDRs, fails to show both early changes in VDR gene expression and later changes in growth with 1,25(OH)(2) D-3. To assess the role of the VDR more directly, transfection studies were pursued. ALVA-31 cells were stably transfected with an antisense VDR cDNA construct in an attempt to reduce VDR expression. Antisense mRNA expression among clones was associated with: (a) reduced or abolished sensitivity to the effects of 1,25(OH)(2) D-3 on growth; (b) decreased numbers of VDRs per cell, as measured by radiolabelled-ligand binding; and (c) a lack of induction of the VDR-regulated enzyme 24-hydroxylase in response to 1,25(OH)(2) D-3. From these studies we conclude that the antiproliferative effects of 1,25(OH)(2) D-3 require expression of the nuclear VDR in this system. Copyright (C) 1996 Elsevier Science Ltd.