Evidence for Involvement of Nonclassical Pathways in the Protection From UV-Induced DNA Damage by Vitamin D–Related Compounds

The vitamin D hormone, 1,25dihydroxyvitamin D₃ (1,25(OH)₂D₃), and related compounds derived from vitamin D₃ 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 D₃ or 24-hydroxylumisterol_3, as previously shown for 1,25(OH)₂D₃. Treatment with 1,25(OH)₂D₃ 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)₂D₃. The requirement for a vitamin D receptor for the photoprotective actions of 1,25(OH)₂D₃ 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 1α-hydroxylase and thus unable to make 1,25(OH)₂D₃ are not more susceptible.