Abstract |
Human lung tumors aberrantly express the 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3))-catabolizing enzyme, CYP24. We hypothesized that CYP24 reduces 1,25(OH)(2)D(3)-mediated transcription and allows lung cancer cells to escape its growth-inhibitory action. To test this, H292 lung cancer cells and the CYP24-selective inhibitor CTA091 were utilized. In H292 cells, CTA091 reduces 1,25(OH)(2)D(3) catabolism, significantly increases 1,25(OH)(2)D(3)-mediated growth inhibition, and increases 1,25(OH)(2)D(3) effects on induced and repressed genes in gene expression profiling studies. Pathway mapping of repressed genes uncovered cell cycle as a predominant 1,25(OH)(2)D(3) target. In H292 cells, 1,25(OH)(2)D(3) significantly decreases cyclin E2 levels and induces G(0)/G(1) arrest. A broader set of cyclins is down-regulated when 1,25(OH)(2)D(3) is combined with CTA091, and cell cycle arrest further increases. Effects of CTA091 on 1,25(OH)(2)D(3) signaling are vitamin D receptor-dependent. These data provide evidence that CYP24 limits 1,25(OH)(2)D(3) anti-proliferative signaling in cancer cells, and suggest that CTA091 may be beneficial in preserving 1,25(OH)(2)D(3) action in lung cancer.
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Authors | Qiuhong Zhang, Beatriz Kanterewicz, Shama Buch, Martin Petkovich, Robert Parise, Jan Beumer, Yan Lin, Brenda Diergaarde, Pamela A Hershberger |
Journal | Molecular and cellular endocrinology
(Mol Cell Endocrinol)
Vol. 355
Issue 1
Pg. 153-61
(May 15 2012)
ISSN: 1872-8057 [Electronic] Ireland |
PMID | 22386975
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2012 Elsevier Ireland Ltd. All rights reserved. |
Chemical References |
- Cyclins
- Enzyme Inhibitors
- Receptors, Calcitriol
- Steroid Hydroxylases
- Vitamin D3 24-Hydroxylase
- Calcitriol
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Topics |
- Calcitriol
(metabolism, pharmacology)
- Cell Cycle Checkpoints
(drug effects)
- Cell Line, Tumor
- Cyclins
(antagonists & inhibitors, genetics)
- Dose-Response Relationship, Drug
- Enzyme Inhibitors
(pharmacology)
- Gene Expression
(drug effects)
- Gene Expression Profiling
- Humans
- Lung Neoplasms
(enzymology, pathology)
- Receptors, Calcitriol
(genetics, metabolism)
- Signal Transduction
(drug effects)
- Steroid Hydroxylases
(antagonists & inhibitors, metabolism)
- Vitamin D3 24-Hydroxylase
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