Abstract
Acute myeloid leukemia (AML) cell lines can be driven to differentiate to monocyte-like cells by 1,25- dihydroxyvitamin D3 (1,25D) and to granulocyte-like cells by all-trans-retinoic acid (ATRA). Both compounds activate their specific intracellular receptors, vitamin D receptor (VDR) and retinoic acid receptors (RARs) respectively. Inside the cells 1,25D is degraded to calcitrioic acid by a mitochondrial enzyme CYP24A1, while ATRA is degraded to several polar metabolites by CYP26. NADPH-cytochrome P450 oxidoreductase (POR) is a membrane-bound enzyme required for electron transfer to cytochrome P450 (CYP), vital in the processes of the metabolism of drugs and steroid production in humans. In this paper we report that POR in AML cells, from both cell lines and patients, is upregulated by ATRA and by 1,25D at the level of mRNA and protein. Partial silencing of POR in HL60 cells resulted in augmented differentiation response to 1,25D.
Highlights
Retinoic acid (RA) and 1,25-dihydroxyvitamin D3 (1,25D) are highly active signaling molecules, which regulate many important cellular processes including differentiation [1,2]
In our previous paper we demonstrated that various acute myeloid leukemia (AML) cell lines have different susceptibilities to 1,25D- or all-trans-retinoic acid (ATRA)-induced differentiation into monocyte-like or granulocyte-like cells respectively [16]
We observed that in the cells exposed to 1,25D there was no increase in P450 oxidoreductase (POR) level above the untreated sample, while in the cells exposed to ATRA the POR level increased less than in the control shRNA (CtrA) cells (Fig. 3B)
Summary
Retinoic acid (RA) and 1,25-dihydroxyvitamin D3 (1,25D) are highly active signaling molecules, which regulate many important cellular processes including differentiation [1,2]. Upon ligation VDR and RARs undergo conformational changes, that allow binding to specific sequences in the promoter regions of target genes, called retinoic acid response elements (RARE) or vitamin D response elements (VDRE). Since both RA and 1,25D are highly active compounds, their effective concentrations must be strictly regulated in organisms. RAinduced transactivation of CYP26 gene is mediated by RARE, which is present in the CYP26 promoter region [8,9] Another enzyme, which is located in mitochondria, namely CYP24A1, is responsible for degradation of 1,25D to its inactive metabolite, calcitrioic acid. We investigated if POR gene and/or protein are regulated by ATRA and 1,25D in AML blasts from cell lines and from patients with AML
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