Abstract
Deregulated melanogenesis is involved in melanomagenesis and melanoma progression and resistance to therapy. Vitamin D analogs have anti-melanoma activity. While the hypercalcaemic effect of the active form of Vitamin D (1,25(OH)2D3) limits its therapeutic use, novel Vitamin D analogs with a modified side chain demonstrate low calcaemic activity. We therefore examined the effect of secosteroidal analogs, both classic (1,25(OH)2D3 and 25(OH)D3), and novel relatively non-calcemic ones (20(OH)D3, calcipotriol, 21(OH)pD, pD and 20(OH)pL), on proliferation, colony formation in monolayer and soft-agar, and mRNA and protein expression by melanoma cells. Murine B16-F10 and hamster Bomirski Ab cell lines were shown to be effective models to study how melanogenesis affects anti-melanoma treatment. Novel Vitamin D analogs with a short side-chain and lumisterol-like 20(OH)pL efficiently inhibited rodent melanoma growth. Moderate pigmentation sensitized rodent melanoma cells towards Vitamin D analogs, and altered expression of key genes involved in Vitamin D signaling, which was opposite to the effect on heavily pigmented cells. Interestingly, melanogenesis inhibited ligand-induced Vitamin D receptor translocation and ligand-induced expression of VDR and CYP24A1 genes. These findings indicate that melanogenesis can affect the anti-melanoma activity of Vitamin D analogs in a complex manner.
Highlights
Besides its classical role in calcium homeostasis and bone metabolism [1], the active form of Vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), known as calcitriol, demonstrates high therapeutic and prophylactic potential in osteoporosis, psoriasis and autoimmune diseases, to name just a few [2,3]
Previous studies on human melanoma SKMEL-188 cells demonstrated that enhanced melanogenesis attenuated the antiproliferative activity of 20(OH)D3 which was associated with downregulation of Vitamin D receptor (VDR) expression [46]
To better understand the mechanism of differential action of Vitamin D and lumisterol metabolites in relation to the melanogenic pathway, we used two rodent melanoma models in which melanin synthesis is inducible by melanin precursors [47,56,57]
Summary
Besides its classical role in calcium homeostasis and bone metabolism [1], the active form of Vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), known as calcitriol, demonstrates high therapeutic and prophylactic potential in osteoporosis, psoriasis and autoimmune diseases, to name just a few [2,3]. It inhibits growth and induces the differentiation of multiple cell types [4,5]. The resulting previtamin D3 isomerizes via a non-enzymatic reaction producing Vitamin D3 (cholecalciferol, (3β,5Z,7E)-9,10-secocholesta5,7,10(19)-trien-3-ol). UV radiation is the main environmental factor involved in the development of skin cancer, including melanoma
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