Evidence for Involvement of Nonclassical Pathways in the Protection From UV-Induced DNA Damage by Vitamin D-Related Compounds
JBMR PLUS(2021)
Abstract
The vitamin D hormone, 1,25dihydroxyvitamin D-3 (1,25(OH)(2)D-3), and related compounds derived from vitamin D-3 or lumisterol as a result of metabolism via the enzyme CYP11A1, have been shown, when applied 24 hours before or immediately after UV irradiation, to protect human skin cells and skin from DNA damage due to UV exposure, by reducing both cyclobutane pyrimidine dimers (CPD) and oxidative damage in the form of 8-oxo-7,8-dihydro-2 '-deoxyguanosine (8-OHdG). We now report that knockdown of either the vitamin D receptor or the endoplasmic reticulum protein ERp57 by small, interfering RNA (siRNA) abolished the reductions in UV-induced DNA damage with 20-hydroxyvitamin D-3 or 24-hydroxylumisterol(3,) as previously shown for 1,25(OH)(2)D-3. Treatment with 1,25(OH)(2)D-3 reduced oxygen consumption rates in UV-exposed and sham-exposed human keratinocytes and reduced phosphorylation of cyclic AMP response binding element protein (CREB). Both these actions have been shown to inhibit skin carcinogenesis after chronic UV exposure, consistent with the anticarcinogenic activity of 1,25(OH)(2)D-3. The requirement for a vitamin D receptor for the photoprotective actions of 1,25(OH)(2)D-3 and of naturally occurring CYP11A1-derived vitamin D-related compounds may explain why mice lacking the vitamin D receptor in skin are more susceptible to UV-induced skin cancers, whereas mice lacking the 1 alpha-hydroxylase and thus unable to make 1,25(OH)(2)D-3 are not more susceptible. (C) 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Key words
1 alpha,25-DIHYDROXYVITAMIN D-3, LUMISTEROL, UV-INDUCED DNA DAMAGE, VITAMIN D RECEPTOR, ERp57, CREB PHOSPHORYLATION, OXIDATIVE PHOSPHORYLATION
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