TY - JOUR
T1 - The noncalcemic vitamin D analogues EB1089 and 22-oxacalcitriol interact with the vitamin D receptor and suppress parathyroid hormone-related peptide gene expression
AU - Falzon, Miriam
N1 - Funding Information:
I wish to thank Dr Milan Uskokovic, Hoffmann LaRoche, for supplying 1,25-dihydroxyvitamin D 3 , Dr Lise Binderup, Leo Pharmaceuticals, for supplying EB1089, Dr Noboru Kubodera, Chugai Pharmaceutical, for supplying OCT, and Dr I.S.Y. Chen, University of California at Los Angeles for the MT-2 cell line. I also wish to thank Drs D. Konkel, P.K. Seitz, M.L. Thomas and C.S. Watson for critical reading of the manuscript and Dr. S. Peleg for advice with COS 1 cell transfections and extract preparation. This work was supported by research grants from the National Institutes of Health and the American Lung Association.
PY - 1997/3/14
Y1 - 1997/3/14
N2 - Humoral hypercalcemia of malignancy, a frequent complication of squamous cell carcinomas of the lung, is mediated by the parathyroid hormone-related peptide (PTHrP). This study was undertaken to determine whether 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and two nonhypercalcemic analogues, EB1O89 and 22-oxa-1,25(OH)2D3 (OCT), suppress PTHrP gene expression in a human lung squamous cancer cell line, NCI H520. All three compounds (1) decreased steady-state PTHrP mRNA and secreted peptide levels via a transcriptional mechanism; (2) modulated promoter activity of 1,25(0H)2D3-responsive DNA sequences; and (3) activated the vitamin D receptor (VDR) both in vitro and in vivo. Thus, EB1089 and OCT inhibit PTHrP gene expression in NCI H520 cells and modulate gene expression through the same mechanism as 1,25(OH)2D3, namely, activation of the VDR. 1,25(OH)2D3 is hypercalcemic in vivo. However, the noncalcemic analogues EB1089 and OCT have a therapeutic potential through suppression of PTHrP gene transcription.
AB - Humoral hypercalcemia of malignancy, a frequent complication of squamous cell carcinomas of the lung, is mediated by the parathyroid hormone-related peptide (PTHrP). This study was undertaken to determine whether 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and two nonhypercalcemic analogues, EB1O89 and 22-oxa-1,25(OH)2D3 (OCT), suppress PTHrP gene expression in a human lung squamous cancer cell line, NCI H520. All three compounds (1) decreased steady-state PTHrP mRNA and secreted peptide levels via a transcriptional mechanism; (2) modulated promoter activity of 1,25(0H)2D3-responsive DNA sequences; and (3) activated the vitamin D receptor (VDR) both in vitro and in vivo. Thus, EB1089 and OCT inhibit PTHrP gene expression in NCI H520 cells and modulate gene expression through the same mechanism as 1,25(OH)2D3, namely, activation of the VDR. 1,25(OH)2D3 is hypercalcemic in vivo. However, the noncalcemic analogues EB1089 and OCT have a therapeutic potential through suppression of PTHrP gene transcription.
KW - 1,25-dihydroxyvitamin D
KW - 22-oxacalcitriol
KW - D
KW - EB1089
KW - Parathyroid hormone-related peptide
KW - Transcription
KW - Vitamin D receptor
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U2 - 10.1016/S0303-7207(96)03994-9
DO - 10.1016/S0303-7207(96)03994-9
M3 - Article
C2 - 9099905
AN - SCOPUS:0030972630
SN - 0303-7207
VL - 127
SP - 99
EP - 108
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
IS - 1
ER -