1α,25-dihydroxyvitamin D3 inhibits prostate cancer cell growth by androgen-dependent and androgen-independent mechanisms

We recently reported that 1 alpha,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] inhibits the growth of the LNCaP human prostate cancer cell line by an androgen-dependent mechanism. In the present study we examined the actions and interactions of 1,25-(OH)(2)D-3 and the androgen 5 alpha-dihydrotestosterone (DHT) on two new human prostate cancer cell lines (MDA), MDA PCa 2a and MDA PCa 2b. Scatchard analyses revealed that both cell lines express high affinity vitamin D receptors (VDRs) with a binding affinity (K-d) for [H-3]1,25-(OH)(2)D-3 of 0.1 nM. However, the MDA cell lines contain low affinity androgen receptors (ARs) with a K-d of 25 nM for [H-3]DHT binding. This is 50-fold lower than the AR in LNCaP cells (K-d = 0.5 nM). Their response to DHT is greatly reduced; 2a cells do not respond to 100 nM DHT, and 2b cells show a modest response at that high concentration. 1,25-(OH)(2)D-3 causes significant growth inhibition in both MDA cell lines, greater (for 2b cells) or lesser (for 2a cells) than that in the LNCaP cell line. Moreover, 1,25-(OH)(2)D-3 significantly up-regulates AR messenger RNA in all three cell lines, as shown by Northern blot analysis. The growth inhibitory effect of 1,25-(OR)(2)D-3 on LNCaP cells is blocked by the pure antiandrogen, Casodex, as we previously reported. However, Casodex (at 1 mu M) did not block the antiproliferative activity of 1,25-(OH)(2)D-3 in MDA cells. In conclusion, the growth inhibitory action of 1,25(OH)(2)D-3 in the MDA cell lines appears to be androgen independent, whereas the actions of 1,25-(OH)(2)D-3 in LNCaP cells are androgen dependent. Most importantly, the MDA cell lines, derived from a bone metastasis of human prostate carcinoma, remain sensitive to 1,25-(OH)(2)D-3, a finding relevant to the therapeutic application of vitamin D and its low calcemic analogs in the treatment of advanced prostate cancer.