CYP24 inhibition preserves 1α,25-dihydroxyvitamin D3 anti-proliferative signaling in lung cancer cells

Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Molecular and Cellular Endocrinology (Impact Factor: 4.41). 02/2012; 355(1):153-61. DOI: 10.1016/j.mce.2012.02.006
Source: PubMed


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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Available from: Pamela A Hershberger, Dec 03, 2014
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    • "The serum level of 1,25(OH)2D is determined on one hand, from the conversion of the substrate 25(OH)D to the active moiety 1,25(OH)2D by the enzyme 1α-hydroxylase in the kidney, and on the other hand, by its degradation process, the first step of which is the 24-hydroxylation of 1,25(OH)2D. The enzyme 25-hydroxyvitamin D 24-hydroxylase controls degradation of both 25(OH)D into 24,25(OH)2D, and 1,25(OH)2D into 1,24,25(OH)3D [30], [31]. Since currently there is no reliable method to measure 1,24,25(OH)3D, we assessed the 24-hydroxylase activity by measurement of serum 24,25(OH)2D, which was in the normal range and not significantly different in both survivors and non-survivors. "
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