1alpha,25-dihydroxyvitamin D(3) displays divergent growth effects in both normal and malignant cells

Induction of growth arrest and differentiation of some cancer cells by 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], and its potent analogs, is well characterized. However, aggressive cancer cell lines are often either insensitive to the antiproliferative effects of 1alpha,25(OH)(2)D(3) or require toxic concentrations to recapitulate them which has, to-date, precluded its use in anticancer therapy. Therefore we are interested in mechanisms by which 1alpha,25(OH)(2)D(3) signaling has become deregulated in malignant cells in order to identify novel therapeutic targets. We observed previously that 1alpha,25(OH)(2)D(3) and its metabolites, generated via the C-24 oxidation pathway, drive simultaneous differentiation and hyper-proliferation within the same cell population. Thus we have proposed that metabolism of 1alpha,25(OH)(2)D(3) via the C-24 oxidation pathway represents a novel-signaling pathway, which integrates proliferation with differentiation. In the current study we examined further the role of this pathway and demonstrated that these effects are not restricted to leukemic cells but are observed also in both normal myeloid progenitors and breast cancer cell lines. Intriguingly, stable transfection of MCF-7 breast cancer cells with antisense vitamin D(3) receptor (VDR) reduced antiproliferative sensitivity to 1alpha,25(OH)(2)D(3) but significantly enhanced growth stimulation, which, in turn, was blocked by inhibiting metabolism of 1alpha,25(OH)(2)D(3) via C-24 oxidation pathway with ketoconazole. Taken together, these studies indicate that metabolism of 1alpha,25(OH)(2)D(3) via C-24 oxidation pathway gives rise to ligands with different biologic effects. We propose that this mechanism may allow the co-ordination of population expansion and cell maturation during differentiation. Cancer cells appear to corrupt this process during malignant transformation, by only responding to the pro-proliferative signals, thereby deriving a clonal advantage.