Growth inhibitory effects of 1 alpha, 25-dihydroxyvitamin D-3 are mediatedby increased levels of p21 in the prostatic carcinoma cell line ALVA-31

1 alpha, 25-Dihydroxyvitamin D-3 [1 alpha, 25-(OH)(2)D-3] is recognized to have significant antiproliferative effects on certain prostatic carcinoma ( PC) cell lines, although the precise mechanisms of action remain in questio n. We have evaluated the role of the cell cycle-dependent kinase inhibitor p21. In the PC cell lines ALVA-31 and LNCaP, 1 alpha, 25-(OH)(2)D-3 inhibit s growth and induces both p21 mRNA and protein levels. Growth inhibition of ALVA-31 cells was abolished by stable transfection with a p21 antisense co nstruct. This effect was not attributable to a reduction in functional vita min D receptors as measured by transcriptional activity with a luciferase-v itamin D response element reporter construct. Therefore, increased p21 expr ession appears necessary to mediate the antiproliferative effects of this h ormone in ALVA-31 cells. Cell lines that are insensitive to the growth inhi bitory properties of 1 alpha, 25-(OH)(2)D-3 failed to up-regulate p21 expre ssion after hormone treatment; these include sublines of ALVA-31 as well as the cell lines TSU-Pr1 and JCA-1. In the latter two lines, adenovirus-medi ated expression of a sense p21 cDNA significantly reduced their proliferati on as compared with a control adenoviral construct. This suggests that the signaling pathway downstream of p21 is intact in TSU-Pr1 and JCA-1 cells, a lthough p21 expression appears unregulated by la, 25-(OH)(2)D-3. We propose a model in which the antiproliferative effect of 1 alpha, 25-(OH)(2)D-3 on PC cells is mediated through increased p21 expression. Elucidation of why this effect is absent in select cell lines may provide valuable insight int o the variability of responses observed in PC patients treated with vitamin D.