Abstract
Vitamin D is a precursor for secosteroidal hormones, which demonstrate pleiotropic biological activities, including the regulation of growth and the differentiation of normal and malignant cells. Our previous studies have indicated that the inhibition of melanoma proliferation by a short side-chain, low calcemic analog of vitamin D—21(OH)pD is not fully dependent on the expression of vitamin D receptor (VDR). We have examined the effects of classic vitamin D metabolites, 1,25(OH)2D3 and 25(OH)D3, and two low calcemic vitamin D analogs, (21(OH)pD and calcipotriol), on proliferation, mRNA expression and vitamin D receptor (VDR) translocation in three human melanoma cell lines: WM98, A375 and SK-MEL-188b (subline b of SK-MEL-188, which lost responsiveness to 1,25(OH)2D3 and became VDR−/−CYP27B1−/−). All tested compounds efficiently inhibited the proliferation of WM98 and A375 melanoma cells except SK-MEL-188b, in which only the short side-chain vitamin D analog—21(OH)pD was effective. Overall, 21(OH)pD was the most potent compound in all three melanoma cell lines in the study. The lack of responsiveness of SK-MEL-188b to 1,25(OH)2D3, 25(OH)D3 and calcipotriol is explained by a lack of characteristic transcripts for the VDR, its splicing variants as well as for vitamin D-activating enzyme CYP27B1. On the other hand, the expression of VDR and its splicing variants and other vitamin D related genes (RXR, PDIA3, CYP3A4, CYP2R1, CYP27B1, CYP24A1 and CYP11A1) was detected in WM98 and A375 melanomas with the transcript levels being modulated by vitamin D analogs. The expression of VDR isoforms in WM98 cells was stimulated strongly by calcipotriol. The antiproliferative activities of 21(OH)pD appear not to require VDR translocation to the nucleus, which explains the high efficacy of this noncalcemic pregnacalciferol analog in SK-MEL-188b melanoma, that is, VDR−/−. Therefore, we propose that 21(OH)pD is a good candidate for melanoma therapy, although the mechanism of its action remains to be defined.
Highlights
Vitamin D is a naturally occurring hormone precursor, which after activation serves as a pleiotropic regulator of homeostasis on cellular and whole organism levels [1,2]
Activated vitamin D receptor (VDR) forms a heterodimer with retinoid X receptor (RXR), and this complex is translocated to the nucleus where it binds to the VDREs and activates the expression of hundreds of human genes [17,18]
We have investigated the response of three human melanoma cell lines against four vitamin D3 analogs
Summary
Vitamin D is a naturally occurring hormone precursor, which after activation serves as a pleiotropic regulator of homeostasis on cellular and whole organism levels [1,2]. Activated VDR forms a heterodimer with retinoid X receptor (RXR), and this complex is translocated to the nucleus where it binds to the VDREs (vitamin D response elements) and activates the expression of hundreds of human genes [17,18] The activity of this complex is regulated by the recruitment of co-activators or co-repressors to modulate the expression of selected genes, including those participating in the inhibition of cell cycle progression and the stimulation of differentiation and apoptosis [19,20,21,22]. We have investigated the response of three human melanoma cell lines against four vitamin D3 analogs. The cutoff point for significance is defined as p < 0.05 (* p < 0.05, ** p < 0.01, *** p < 0.001)
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