SIMIAN-VIRUS-40, BUT NOT HUMAN PAPILLOMAVIRUS, TRANSFORMATION OF PROSTATIC EPITHELIAL-CELLS RESULTS IN LOSS OF GROWTH-INHIBITION BY 1,25-DIHYDROXYVITAMIN-D-3

In addition to its well known calcemic actions, 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D] exhibits differentiating and antiproliferative effe cts in several types of cancer cells. 1,25(OH)(2)D receptors (VDR) as well as 1,25(OH)(2)D-mediated growth-inhibition have been demonstrated in human prostate cancer cell lines. In order to further develop mode l systems for the study of 1,25(OH)(2)D action and to elucidate the me chanism of growth-inhibition, we studied several human prostate cell l ines immortalized with either simian virus 40 (SV40) or human papillom avirus type 18 (HPV). The SV40-transformed cell lines P69SV40-T and P1 53SV40-T were not growth-inhibited by 1,25(OH)(2)D at concentrations a s high as 100 nM, whereas the HPV-transformed cells PZ-HPV-7 and CA-HP V-10 were growth-inhibited. All cell lines expressed VDR, and VDR mRNA was demonstrated by Northern blot analysis. All cells exhibited induc tion of 24-hydroxylase mRNA, a 1,25(OH)(2)D responsive gene, after 1,2 5(OH)(2)D treatment. In an attempt to understand the apparent dissocia tion of 1,25(OH)(2)D actions in the SV40-transformed cells, we turned to the human prostate cancer cell line DU 145. These cells, like the S V40-transformed cells, are not growth-inhibited but demonstrate induct ion of 24-hydroxylase mRNA after 1,25(OH)(2)D treatment. DU 145 cells contain a mutated retinoblastoma gene (Rb) which contributes to their uncontrolled growth, analogous to the disruption of Rb by SV40 and HPV . We compared DU,145 cells to DU 145 cells transfected with normal Rb (DU 145/Rb). Similar to DU 145, DU 145/Rb cells were not growth-inhibi ted by 1,25(OH)(2)D, while 24-hydroxylase mRNA was induced. These resu lts suggest that divergent pathways mediate the growth-inhibitory effe ct of 1,25(OH)(2)D and its induction of 24-hydroxylase. It also appear s that the antiproliferative effect of 1,25(OH)(2)D is mediated by an Rb-independent mechanism.