In vitro comparison of the vitamin D endocrine system in 1,25(OH)2D3-responsive and -resistant melanoma cells

We studied effects of 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], its analog seocalcitol (EB 1089), and 25-hydroxyvitamin D-3 [25(OH)D-3], on the growth of seven melanoma cell lines. While three cell lines (MeWo, SK-Mel-28, SM) responded to antiproliferative effects of active vitamin D analogs, the others (SK-Mel-5, SK-Mel-25, IGR, Melluso) were resistant. A strong induction (7000-fold) of 1,25-dihydroxyvitamin D-24-hydroxylase (24OHase, CYP24) mRNA was detected in responsive cell lines along with 1,25(OH)(2)D-3-treatment, indicating functional integrity of vitamin D receptor (VDR)-mediated transcription. In contrast, induction of 24OHase was much lower in resistant melanoma cells (70-fold). VDR mRNA was induced up to 3-fold both in responsive and resistant cell lines along with 1,25(OH)(2)D-3-treatment. RNA for vitamin D-activating enzymes vitamin D-25-hydroxylase (25OHase, CYP27A1) and 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha OHase, CYP27B1) was detected in all melanoma cell lines analyzed, additionally we show splicing variants of 1 alpha OHase in SK-Mel-28 cells. Expression of 25OHase and 1 alpha OHase was marginally modulated along with treatment. Proliferation of melanoma cells was not inhibited by treatment with 25(OH)D-3, indicating no significant stimulation of endogeneous production of antiproliferative acting 1,25(OH)(2)D-3. In conclusion, we characterize the vitamin D endocrine system in melanoma cells and demonstrate that the majority of melanoma cell lines analyzed is resistant to antiproliferative effects of 1,25(OH)(2)D-3. It can be speculated that these alterations are of importance for pathogenesis and growth of metastasizing malignant melanoma. Additionally, our findings indicate that only a minority of cases with metastasizing melanoma may represent a promising target for palliative treatment with new vitamin D analogs that exert little calcemic side effects or for pharmacological modulation of 1,25(OH)(2)D-3-synthesis/metabolism.