TY - JOUR
T1 - The C-24 metabolites of 1alpha,25-dihydroxyvitamin D(3) display divergent growth effects in both normal and malignant cells
AU - Rashid, SF
AU - Mountford, Joanne
AU - Gombart, AF
AU - Campbell, Moray
PY - 2001/1/1
Y1 - 2001/1/1
N2 - Induction of growth arrest and differentiation of some cancer cells by 1 alpha ,25-dihydroxyvitamin D-3 [1 alpha ,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 1 alpha ,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 1 alpha ,25(OH)(2)D-3 signaling has become deregulated in malignant cells in order to identify novel therapeutic targets. We observed previously that 1 alpha ,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 1 alpha ,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 antisence vitamin D-3 receptor (VDR) reduced antiproliferative sensitivity to 1 alpha ,25(OH)(2)D-3 but significantly enhanced growth stimulation, which, in turn, was blocked by inhibiting metabolism of 1 alpha ,25(OH)(2)D-3 via C-24 oxidation pathway with ketoconazole. Taken together, these studies indicate that metabolism of 1 alpha ,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. (C) 2001 Elsevier Science Inc. All rights reserved.
AB - Induction of growth arrest and differentiation of some cancer cells by 1 alpha ,25-dihydroxyvitamin D-3 [1 alpha ,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 1 alpha ,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 1 alpha ,25(OH)(2)D-3 signaling has become deregulated in malignant cells in order to identify novel therapeutic targets. We observed previously that 1 alpha ,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 1 alpha ,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 antisence vitamin D-3 receptor (VDR) reduced antiproliferative sensitivity to 1 alpha ,25(OH)(2)D-3 but significantly enhanced growth stimulation, which, in turn, was blocked by inhibiting metabolism of 1 alpha ,25(OH)(2)D-3 via C-24 oxidation pathway with ketoconazole. Taken together, these studies indicate that metabolism of 1 alpha ,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. (C) 2001 Elsevier Science Inc. All rights reserved.
KW - cyp24
KW - vitamin D-3
KW - proliferation
KW - cancer cells
UR - http://www.scopus.com/inward/record.url?scp=0035342702&partnerID=8YFLogxK
U2 - 10.1016/S0039-128X(00)00203-8
DO - 10.1016/S0039-128X(00)00203-8
M3 - Article
C2 - 11179752
SN - 0039-128X
VL - 66
SP - 433
EP - 440
JO - Steroids
JF - Steroids
ER -