The Journal of Steroid Biochemistry and Molecular Biology
Skin cancer prevention: A possible role of 1,25dihydroxyvitamin D3 and its analogs
Introduction
Exposure to ultraviolet radiation (UVR) leads to a variety of responses in skin including several types of DNA damage, particularly mutagenic cyclobutane pyrimidine dimers (CPD) [1]. Repair of CPD prevents them from causing a mutation and increased expression of p53 protein in the nucleus enhances this repair partly by increasing the time to cell division. If the DNA damage is irreparable, the cell undergoes apoptosis [2]. In addition, UVR causes suppression of cell-mediated immunity, that becomes irreversible in chronically UVR-exposed skin and facilitates skin cancer outgrowth [3]. UVR also stimulates the formation of pre-Vitamin D from 7-dehydrocholesterol in skin. The pre-Vitamin D thermally isomerizes to Vitamin D [4]. There is evidence that the entire pathway to 1,25dihydroxyvitamin D3 (1,25(OH)2D3) is present in skin [5].
Previous studies in this laboratory, as well as others, showed that 1,25(OH)2D3 markedly inhibited UVR-induced apoptosis in human skin cells [6], [7], [8], [9]. This appears to be associated with a reduction in pro-apoptotic pathways. Since we have demonstrated in preliminary work that CPD DNA damage is reduced soon after UVR exposure in 1,25(OH)2D3-treated cells compared with vehicle-treated cells [9], this may lead to a reduction in apoptotic signals.
The active Vitamin D hormone, 1,25(OH)2D3, like many steroid hormones, appears to exert the full spectrum of its functional effects through two main pathways. One is the classical or genomic pathway, in which the hormone binds to the Vitamin D receptor which then dimerizes with the retinoid X receptor and the complex then binds to the Vitamin D response element on the promoter region of target genes, resulting in an increase or a decrease in transcription of those genes [10]. The second major pathway, the rapid or non-genomic pathway, involves the hormone binding to a membrane receptor, the identity of which is still not resolved [10], [11], stimulating a variety of intracellular signal pathways such as intracellular calcium, protein kinase C, MAP kinase, some or all of which may be implicated in any particular response. One method of differentiating between these functional pathways involves the use of Vitamin D analogs with different conformations. The cis-locked analog 1α,25(OH)2lumisterol3 (JN), which has little calcemic activity, can activate only the rapid response pathway. The compound 1β,25(OH)2D3 (HL) acts only as a rapid response antagonist, whilst (23S)-25-dehydro-1α-hydroxyvitamin D3–26,23-lactone (TEI-9647) acts as a genomic antagonist [12]. We presented preliminary data which were consistent with the proposal that the photoprotective effects of 1,25(OH)2D3 were acting through the rapid, or non-genomic pathway [9] and now provide further data to support this hypothesis. Since any potential use of 1,25(OH)2D3 is limited by its capacity to cause hypercalcemia, we also investigated whether another low calcemic Vitamin D hybrid analog, which has some transactivating capacity, 1α-hydroxymethyl-16-ene-24,24-difluoro-25-hydroxy-26,27-bis-homovitamin D3, QW-1624F2-2 (QW) [13] also showed photoprotective activity. For the first time, preliminary results showing a protective effect of Vitamin D compounds on DNA photodamage in vivo are presented.
Section snippets
Methods
Skin cells from human neonatal foreskins were cultured in 96-well plates on 5 mm glass coverslips coated with poly-l-lysine as described in [14]. Melanocytes were grown in EMEM with 5% (v/v) FBS, supplemented with PMA and cholera toxin. Experiments were carried out at 60–80% confluence and melanocyte culture medium changed to EMEM without supplements at least 2 days before experiments to allow cell signaling pathways to normalize. Fibroblasts were cultured in DMEM with 5% (v/v) FBS.
The UVR
Effects of TEI-9647 and HL on UV-induced cell loss
In human melanocytes treated with HL, the mean UVR-induced cell loss was 28 ± 7%, which was not significantly different from mean cell loss in vehicle-treated cells, 33 ± 6%. Whilst melanocytes treated with 1,25(OH)2D3 had significantly decreased cell loss (mean 13 ± 3%) in comparison to vehicle-treated cells, melanocytes treated with a combination of HL and 1,25(OH)2D3 had mean cell loss of 31 ± 9%, which was not significantly different from loss in vehicle-treated cells.
Cells treated before and after
Discussion
These results confirm that 1,25(OH)2D3, as well as two low calcemic analogs, JN and QW are photoprotective and reduce UVR-induced CPD and cell death in human skin cells in culture. Since CPD and other forms of DNA photodamage occur, resulting either in growth arrest and DNA repair or apoptosis [18], it seems reasonable to propose that the improved cell survival was secondary to reduced DNA damage. This implies better DNA repair, although there is no direct evidence of this as yet. In this
Acknowledgements
This work was supported by grants from the Cancer Council of NSW and the National Health and Medical Research Council of Australia.
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