THE ANTIPROLIFERATIVE EFFECT OF VITAMIN-D-3 ANALOGS IS NOT MEDIATED BY INHIBITION OF THE AP-1 PATHWAY, BUT MAY BE RELATED TO PROMOTER SELECTIVITY

The hormone 1,25-dihydroxyvitamin D-3 (VD) is able to induce cellular differentiation and to inhibit cellular proliferation, which provides it with an interesting therapeutic potential in cancer. However, side effects of VD on homeostasis (eg hypercalcemia) had made the need for the development of VD analogues with low calcemic effect. On the human breast cancer cell line MCF-7 we obtained with the VD analogue EB1089 an about 100-fold higher anti-proliferative effect than with VD. We f ound that this difference in biological activity is neither related to increased functional affinity to the VD receptor nor to repression of AP-1 activity. The physiologically most prominent complex of the VD r eceptor is a heterodimer with the retinoid X receptor that binds VD re sponse elements formed two hexameric core binding motifs being arrange d either as direct repeats spaced by 3 nucleotides (DR3s) or as invert ed palindromes spaced by 9 nucleotides (IP9s). We observed that EB1089 stimulates transcriptional activation from IP9-type elements at clear ly lower concentrations than from DR3-type elements. It is possible th at IP9-type response elements play an important role in or contribute to the control of cell proliferation, so that promoter-selectivity may explain the high anti-proliferative effect of EB1089.