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

Warusavithana Gunawardena Manori De Silva, Jeremy Zhuo Ru Han, Chen Yang, Wannit Tongkao-On, Bianca Yuko McCarthy, Furkan Akif Ince, Andrew J.A. Holland, Robert Charles Tuckey, Andrzej T. Slominski, Myriam Abboud, Katie Marie Dixon, Mark Stephen Rybchyn, Rebecca Sara Mason

Research output: Contribution to journalConference articlepeer-review

Abstract

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-hydroxylumisterol3, 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.

Original languageEnglish
JournalJBMR Plus
DOIs
Publication statusE-pub ahead of print - 13 Sep 2021

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