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

摘要

Human lung tumors aberrantly express the 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2D 3)-catabolizing enzyme, CYP24. We hypothesized that CYP24 reduces 1,25(OH) 2D 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) 2D 3 catabolism, significantly increases 1,25(OH) 2D 3-mediated growth inhibition, and increases 1,25(OH) 2D 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) 2D 3 target. In H292 cells, 1,25(OH) 2D 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) 2D 3 is combined with CTA091, and cell cycle arrest further increases. Effects of CTA091 on 1,25(OH) 2D 3 signaling are vitamin D receptor-dependent. These data provide evidence that CYP24 limits 1,25(OH) 2D 3 anti-proliferative signaling in cancer cells, and suggest that CTA091 may be beneficial in preserving 1,25(OH) 2D 3 action in lung cancer.