TY - JOUR
T1 - Prostate cancer cell type-specific regulation of the human PTHrP gene via a negative VDRE
AU - Tovar Sepulveda, Veronica A.
AU - Falzon, Miriam
N1 - Funding Information:
We thank Dr Milan Uskokovic, Hoffman La Roche, for supplying 1,25-dihydroxyvitamin D 3 , and Dr Lise Binderup, Leo Pharmaceuticals, for providing EB1089. We also thank Dr D. Konkel, Dr P.K. Seitz, and Dr M. L. Thomas for critical reading of the manuscript. This work was supported by NIH grant CA83940.
PY - 2003/6/30
Y1 - 2003/6/30
N2 - Parathyroid hormone-related protein (PTHrP) is expressed by prostate cancer cells. Since PTHrP increases the growth and enhances the osteolytic effects of prostate cancer cells, it is important to control the level of PTHrP expression in these cells. We show that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its non-calcemic analogue, EB1089, suppress PTHrP mRNA and protein levels in the human prostate cancer cell lines PC-3 and LNCaP. The human PTHrP gene contains a sequence element homologous to the negative vitamin D response element within the parathyroid hormone gene. This DNA sequence (nVDREhPTHrP) bound the vitamin D receptor (VDR) present in nuclear extracts from both PC-3 and LNCaP cells. However, when cloned upstream of the SV40 promoter and transiently transfected into PC-3 and LNCaP cells, nVDREhPTHrP downregulated promoter activity in response to 1,25(OH)2D3 or EB1089 treatment in LNCaP, but not in PC-3, cells. These results may help to explain why some prostate cancers appear to be refractory to treatment with vitamin D analogues.
AB - Parathyroid hormone-related protein (PTHrP) is expressed by prostate cancer cells. Since PTHrP increases the growth and enhances the osteolytic effects of prostate cancer cells, it is important to control the level of PTHrP expression in these cells. We show that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its non-calcemic analogue, EB1089, suppress PTHrP mRNA and protein levels in the human prostate cancer cell lines PC-3 and LNCaP. The human PTHrP gene contains a sequence element homologous to the negative vitamin D response element within the parathyroid hormone gene. This DNA sequence (nVDREhPTHrP) bound the vitamin D receptor (VDR) present in nuclear extracts from both PC-3 and LNCaP cells. However, when cloned upstream of the SV40 promoter and transiently transfected into PC-3 and LNCaP cells, nVDREhPTHrP downregulated promoter activity in response to 1,25(OH)2D3 or EB1089 treatment in LNCaP, but not in PC-3, cells. These results may help to explain why some prostate cancers appear to be refractory to treatment with vitamin D analogues.
KW - 1,25-Dihydroxyvitamin D
KW - EB1089
KW - EMSA
KW - LNCaP (prostate cancer cells)
KW - Negative vitamin D response element
KW - PC-3 (prostate cancer cells)
KW - Parathyroid hormone-related protein
KW - Promoter activity
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U2 - 10.1016/S0303-7207(03)00148-5
DO - 10.1016/S0303-7207(03)00148-5
M3 - Article
C2 - 12850281
AN - SCOPUS:0037769114
SN - 0303-7207
VL - 204
SP - 51
EP - 64
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
IS - 1-2
ER -