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

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• 作者：Qiuhong Zhang^a ; Beatriz Kanterewicz^b ; Shama Buch^c ; Martin Petkovich^d ; ^e ; Robert Parise^f ; Jan Beumer^b ; ^f ; Yan Lin^g ; ^h ; Brenda Diergaarde^b ; ⁱ ; Pamela A. Hershberger^a ; ^b ; ^{pamela.hershberger@roswellpark.org}
• 关键词：1 ; 25(OH)2D3 ; 1伪 ; 25-dihydroxyvitamin D3 ; CSS ; charcoal-stripped serum ; CYP24 ; 1伪 ; 25-dihydroxyvitamin D324-hydroxylase ; CTA091 ; MK-24(S)-S(O)(NH)-Ph-1 ; PBS ; phosphate buffered saline ; VDR ; vitamin D receptor ; VDRE ; vitamin D response element
• 刊名：Molecular and Cellular Endocrinology
• 出版年：2012
• 期刊代码：109_03037207
• 类别：bio
• 出版时间：15 May, 2012
• 卷：355
• 期：1
• 页码：153-161
• 文件大小：729 K

摘要

Human lung tumors aberrantly express the 1伪,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃)-catabolizing enzyme, CYP24. We hypothesized that CYP24 reduces 1,25(OH)₂D₃-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)₂D₃ catabolism, significantly increases 1,25(OH)₂D₃-mediated growth inhibition, and increases 1,25(OH)₂D₃ 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)₂D₃ target. In H292 cells, 1,25(OH)₂D₃ significantly decreases cyclin E2 levels and induces G₀/G₁ arrest. A broader set of cyclins is down-regulated when 1,25(OH)₂D₃ is combined with CTA091, and cell cycle arrest further increases. Effects of CTA091 on 1,25(OH)₂D₃ signaling are vitamin D receptor-dependent. These data provide evidence that CYP24 limits 1,25(OH)₂D₃ anti-proliferative signaling in cancer cells, and suggest that CTA091 may be beneficial in preserving 1,25(OH)₂D₃ action in lung cancer.