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Differential biological effects of 1,25-dihydroxyVitamin D3 on melanoma cell lines in vitro
Markus Seifert1, Martin Rech, Viktor Meineke
1Department of Dermatology, The Saarland University Hospital, Homburg, Germany.
Abstract:
1,25-DihydroxyVitamin D(3) and analogs have been shown to inhibit proliferation and to induce differentiation in different cell types, including human melanocytes. However, various tumor cell lines that fail to respond to the antiproliferative effects of Vitamin D analogs have also been reported. Using real-time PCR (LightCycler), we have compared mRNA expression of Vitamin D receptor (VDR), Vitamin D-25-hydroxylase (25-OHase), 25-hydroxyVitamin D-1alpha-hydroxylase (1alpha-OHase), and 1,25-dihydroxyVitamin D-24-hydroxylase (24-OHase) in a melanoma cell line that responds to antiproliferative effects of Vitamin D (MeWo) with a non-responsive melanoma cell line (SkMel5). Additionally, modulation of cell proliferation by calpain inhibitors, as well as regulation of mRNA expression of VDR, 1alpha-OHase, and 24-OHase genes by Vitamin D analogs were assessed in melanoma cell lines in vitro using a WST-1 based colorimetric assay and real-time PCR, respectively. RNA for VDR, 25-OHase, 1alpha-OHase, and 24-OHase was detected in melanoma cell lines. In contrast to SkMel5 cells, treatment of MeWo cells with calcitriol resulted in a dose-dependent increase in mRNA for VDR and 24-OHase as well as in a suppression of cell proliferation (up to approximately 50%). Our findings demonstrate that local synthesis or metabolism of Vitamin D metabolites may be of importance for growth regulation of MM and melanoma cell lines. Additionally, metastasizing MM represents a promising target for palliative treatment with new Vitamin D analogs that exert little calcemic side effects or for pharmacological modulation of calcitriol synthesis/metabolism in these tumors.
Insights
Vitamin D analogs inhibit melanoma cell proliferation by regulating Vitamin D receptor (VDR) and 24-hydroxylase (24-OHase) gene expression. This suggests potential for new Vitamin D therapies for metastatic melanoma.
Area of Science:
- Molecular Biology
- Dermatology
- Endocrinology
Background:
- 1,25-DihydroxyVitamin D(3) and its analogs inhibit proliferation and induce differentiation in various cell types, including melanocytes.
- Some tumor cell lines, however, do not respond to the antiproliferative effects of Vitamin D analogs.
- The role of local Vitamin D metabolism in melanoma growth regulation requires further investigation.
Purpose of the Study:
- To compare mRNA expression of Vitamin D receptor (VDR) and key hydroxylases (25-OHase, 1alpha-OHase, 24-OHase) in responsive (MeWo) versus non-responsive (SkMel5) melanoma cell lines.
- To assess the modulation of melanoma cell proliferation and gene expression by Vitamin D analogs and calpain inhibitors in vitro.
- To explore the potential of Vitamin D analogs for treating metastatic melanoma.
Main Methods:
- Real-time PCR (LightCycler) was used to quantify mRNA expression of VDR, 25-OHase, 1alpha-OHase, and 24-OHase.
- A WST-1 based colorimetric assay was employed to measure cell proliferation.
- Melanoma cell lines (MeWo and SkMel5) were treated with calcitriol and calpain inhibitors.
Main Results:
- Both responsive (MeWo) and non-responsive (SkMel5) melanoma cell lines expressed RNA for VDR, 25-OHase, 1alpha-OHase, and 24-OHase.
- Calcitriol treatment of MeWo cells led to a dose-dependent increase in VDR and 24-OHase mRNA and suppressed cell proliferation by up to 50%.
- SkMel5 cells did not exhibit similar responses to calcitriol treatment.
Conclusions:
- Local synthesis or metabolism of Vitamin D metabolites plays a significant role in regulating the growth of melanoma cell lines.
- Responsive melanoma cells show increased VDR and 24-OHase mRNA expression and reduced proliferation upon calcitriol treatment.
- Metastatic melanoma is a potential target for novel Vitamin D analogs with minimal calcemic side effects or for modulating calcitriol metabolism.
