CYP24 inhibition preserves 1α,25-dihydroxyvitamin D(3) anti-proliferative signaling in lung cancer cells.

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.

• 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)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Cyclins
• Enzyme Inhibitors
• Receptors, Calcitriol
• Steroid Hydroxylases
• Vitamin D3 24-Hydroxylase
• Calcitriol

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