Vitamin D receptor content and transcriptional activity do not fully predict antiproliferative effects of vitamin D in human prostate cancer cell lines

Prostate cancer cell lines exhibit variable growth suppression by the hormonal form of vitamin D-3, 1,25-Dihydroxyvitamin D-3 [1,25 (OH)(2)D] (1,25 D-3). To understand the molecular basis for this differential sensitivity to 1,25 D-3, we compared growth response to 1,25 D-3, vitamin D receptor (VDR) content and VDR transcriptional activity in four well-characterized human prostate cancer cell lines: LNCaP, DU145, PC-3 and ALVA-31. In PC-3 and DU145 cells, relative lack of growth inhibition by 1,25 D-3 (<10% inhibition) correlates with very low levels of VDR (9-15 fmol/mg protein) compared to classical vitamin D-3 target tissues (similar to 75-200 fmol/mg protein). Transfection of DU145 and PC-3 cells with a VDR cDNA expression vector is sufficient to establish growth sensitivity to 1,25 D-3, suggesting that low VDR levels are responsible for the failure of these cell lines to respond to 1,25 D-3. LNCaP cells are highly sensitive to growth inhibition by 1,25 D-3 (similar to 55% inhibition) and contain similar to 2-3-fold more VDR (25 fmol/mg) than the relatively 1,25 D-3-insensitive PC-3 and DU145 cell lines. However, ALVA-31 cells display less than 20% growth inhibition to 1,25 D-3 although they contain the highest levels of VDR (45 fmol/mg) of the four cell lines. Thus, sensitivity to growth inhibition by 1,25 D-3 does not correlate with VDR content in ALVA-31 and LNCaP cells. This lack of correlation between VDR density and growth responses to 1,25 D-3 led us to investigate VDR-mediated gene transcription in these cell lines. We employed two different naturally-occurring vitamin D response elements (VDREs) linked to a reporter gene. Reporter gene activation by 1,25 D-3 correlated well with VDR content in all four cell lines. Therefore, compared to LNCaP cells, decreased sensitivity of ALVA-31 to growth inhibition by 1,25 D-3 is not due to a decrease in the general transcriptional activity of VDR. We conclude that growth inhibition by 1,25 D-3 in prostate cancer cells requires VDR but that this response is modulated by non-receptor factors that are cell line-specific. Copyright (C) 1997 Elsevier Science Ireland Ltd.