Antiproliferative Activity of Non-Calcemic Vitamin D Analogs on Human Melanoma Lines in Relation to VDR and PDIA3 Receptors

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.

Vitamin D3 Ameliorates DNA Damage Caused by Developmental Exposure to Endocrine Disruptors in the Uterine Myometrial Stem Cells of Eker Rats

“…Our observation that VitD3 significantly decreased the proliferation of DES-MMSCs suggests a potential role for VitD3 in reducing tumor development ( Figure S4 ). Our current findings are also in agreement with previously published data [ 69 , 70 ].…”

Effects of vitamin D in the nervous system: Special focus on interaction with steroid hormone signalling and a possible role in the treatment of brain cancer

“…1,25‐Dihydroxyvitamin D 3 ‐mediated suppression of migration and proliferation in T98G cells was also reported by Emanuelsson et al In addition to physiological 1,25‐dihydroxyvitamin D 3 , Emanuelsson et al investigated the responses to calcipotriol and tacalcitol, two commercially available vitamin D analogues that are used clinically in the topical treatment of psoriasis . These two analogues have been examined in several cancer cell lines outside the nervous system and have been shown to suppress proliferation and migration via different mechanisms . Both compounds, in particular calcipotriol, have less calcaemic side effects than physiological vitamin D .…”

Relevance of Vitamin D in Melanoma Development, Progression and Therapy

“…A very recent report showed anti-melanoma activity of 21(OH)pD in WM98, A375 and SK-MEL-188b (VDR −/− CYP27B1 −/− ) lines. Only WM98 and A375 cells were sensitive to calcipotriol (184). (196), and 1(OH)D 2 reduced tumor growth in Tyr-Tag transgenic mice, which develop pigmented ocular tumors, similar to human choroidal melanoma (205).…”