Stable expression of the nuclear vitamin D receptor in the human prostatic carcinoma cell line JCA-1: evidence that the antiproliferative effects of 1 alpha, 25-dihydroxyvitamin D3 are mediated exclusively through the genomic signaling pathway.
The secosteroid hormone 1 alpha, 25-dihydroxyvitamin D3 [1,25-(OH)2D3] has been found to regulate the growth and differentiation of human prostate cancer cells, although the precise mechanisms mediating these effects have not been defined. 1,25-(OH)2D3 is capable of acting through both nongenomic signaling pathways involving a membrane-associated receptor and genomic pathways involving the nuclear vitamin D receptor (VDR). The primary purpose of this study was to directly evaluate the role of the nuclear VDR in mediating the growth inhibitory effects of 1,25-(OH)2D3 on human prostate cancer cells. The cell line JCA-1 was used because it fails to express detectable number of VDRs and is not measurable affected by 1,25-(OH)2D3 in growth studies. These cells were stably transfected with a wild-type VDR complementary DNA construct producing the following results: 1) the expression of high affinity nuclear VDRs, 2) the dose-dependent inhibition of growth by 1,25-(OH)2D3, and 3) a significant increase in 24-hydroxylase up-regulation by 1,25-(OH)2D3 compared to that in controls. These data indicate that nuclear VDR expression is sufficient to mediate the antiproliferative effects of 1,25-(OH)2D3 on prostate cancer cells. In addition, because the stereoisomer 1 beta, 25-dihydroxyvitamin D3 failed to block these antiproliferative effects, we conclude that nongenomic mechanisms of action are not requisite for growth inhibition by 1,25-(OH)2D3.
Hedlund
T E
TE
Department of Pathology, University of Colorado Health Sciences Center, Denver 80262, USA.
Moffatt
K A
KA
Miller
G J
GJ
D001483:Base Sequence; D002117:Calcitriol / Q000008:administration & dosage / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D011471:Prostatic Neoplasms / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects*; D013237:Stereoisomerism; D013250:Steroid Hydroxylases / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D065668:Vitamin D3 24-Hydroxylase
D018167:Receptors, Calcitriol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol