1α,25 Dihydroxyvitamin D3 enhances cellular defences against UV-induced oxidative and other forms of DNA damage in skin

Gordon-Thomson, Clare; Gupta, Ritu; Tongkao-on, Wannit; Ryan, Anthony A.; Halliday, Gary M.; Mason, Rebecca S.

doi:10.1039/c2pp25202c

Cited by 68 publications

(74 citation statements)

References 74 publications

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“…These results were intriguing because delayed CPD production had occasionally been reported in other cell types after UVC or UVB exposure [15–19], often with wide variability. It seemed possible that the melanin-dependent mechanism would be more susceptible to experimental study.…”

Section: Cpds In the Darkmentioning

confidence: 87%

Chemical excitation of electrons: A dark path to melanoma

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Brash

2016

DNA Repair

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Sunlight’s ultraviolet wavelengths induce cyclobutane pyrimidine dimers (CPDs), which then cause mutations that lead to melanoma or to cancers of skin keratinocytes. In pigmented melanocytes, we found that CPDs arise both instantaneously and for hours after UV exposure ends. Remarkably, the CPDs arising in the dark originate by a novel pathway that resembles bioluminescence but does not end in light: First, UV activates the enzymes nitric oxide synthase (NOS) and NADPH oxidase (NOX), which generate the radicals nitric oxide (NO•) and superoxide (O2•−); these combine to form the powerful oxidant peroxynitrite (ONOO−). A fragment of the skin pigment melanin is then oxidized, exciting an electron to an energy level so high that it is rarely seen in biology. This process of chemically exciting electrons, termed “chemiexcitation”, is used by fireflies to generate light but it had never been seen in mammalian cells. In melanocytes, the energy transfers radiationlessly to DNA, inducing CPDs. Chemiexcitation is a new source of genome instability, and it calls attention to endogenous mechanisms of genome maintenance that prevent electronic excitation or dissipate the energy of excited states. Chemiexcitation may also trigger pathogenesis in internal tissues because the same chemistry should arise wherever superoxide and nitric oxide arise near cells that contain melanin.

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Section: Cpds In the Darkmentioning

confidence: 87%

Chemical excitation of electrons: A dark path to melanoma

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Brash

2016

DNA Repair

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“…S2D). The melanin requirement suggests that the NO • requirement in melanocytes is distinct from that observed in cultured keratinocytes (18). Peroxynitrite's presence in the nucleus without UV exposure is plausible because synthesis of melanin monomers is a redox reaction that releases O 2 •– (7) and melanosomes are assembled in the perinuclear space.…”

Section: Photochemical Pathwaymentioning

confidence: 99%

Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure

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Wallisch

Mano

et al. 2015

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Mutations in sunlight-induced melanoma arise from cyclobutane pyrimidine dimers (CPD), DNA photoproducts that are typically created picoseconds after an ultraviolet (UV) photon is absorbed at thymine or cytosine. Here we show that in melanocytes, CPD are generated for >3 hours after exposure to UVA, a major component of the radiation in sunlight and in tanning beds. These “dark CPD” constitute the majority of CPD and include the cytosine-containing CPD that initiate UV-signature C→T mutations. Dark CPD arise when UV-induced reactive oxygen and nitrogen species combine to excite an electron in fragments of the pigment melanin. This creates a quantum triplet state that has the energy of a UV photon but that induces CPD by energy transfer to DNA in a radiation-independent manner. Melanin may thus be carcinogenic as well as protective against cancer. These findings also validate the long-standing suggestion that chemically-generated excited electronic states are relevant to mammalian biology.

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“…VDR and CYP27B1 expression in mammary adipocytes also contribute to the anti-cancer effects in the whole tissue, since in response to 25(OH)D adipocytes secrete diffusible signals that inhibit morphogenesis of the adjacent ductal epithelium (Ching et al, 2011). Other potential mechanisms for breast cancer prevention by vitamin D include reduction in DNA damage (possibly via up-regulation of p53 signaling), suppression of oxidative stress and inhibition of angiogenesis, many of which have been demonstrated in tissues or cell types other than mammary gland (Kallay et al, 2002; Peng et al, 2010; Bruce et al, 2011; Hopkins et al, 2011; Krishnan and Feldman, 2011; Bikle, 2012; Dogan et al, 2012; Gordon-Thomson et al, 2012; Ting et al, 2012; Alvarez et al, 2014; Nakai et al, 2014; Sun et al, 2014; Uberti et al, 2014; Zhong et al, 2014). In addition, recent data from our group and others implicate alteration of cellular energy metabolism and innate immune responses in the anti-cancer effects of vitamin D signaling on non-tumorigenic mammary epithelial cells as described below.…”

Section: Vitamin D Pathway Expression In Normal Mammary Cells and Brementioning

confidence: 99%

The impact of vitamin D in breast cancer: genomics, pathways, metabolism

et al. 2014

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Nuclear receptors exert profound effects on mammary gland physiology and have complex roles in the etiology of breast cancer. In addition to receptors for classic steroid hormones such as estrogen and progesterone, the nuclear vitamin D receptor (VDR) interacts with its ligand 1α,25(OH)2D3 to modulate the normal mammary epithelial cell genome and subsequent phenotype. Observational studies suggest that vitamin D deficiency is common in breast cancer patients and that low vitamin D status enhances the risk for disease development or progression. Genomic profiling has characterized many 1α,25(OH)2D3 responsive targets in normal mammary cells and in breast cancers, providing insight into the molecular actions of 1α,25(OH)2D3 and the VDR in regulation of cell cycle, apoptosis, and differentiation. New areas of emphasis include regulation of tumor metabolism and innate immune responses. However, the role of VDR in individual cell types (i.e., epithelial, adipose, fibroblast, endothelial, immune) of normal and tumor tissues remains to be clarified. Furthermore, the mechanisms by which VDR integrates signaling between diverse cell types and controls soluble signals and paracrine pathways in the tissue/tumor microenvironment remain to be defined. Model systems of carcinogenesis have provided evidence that both VDR expression and 1α,25(OH)2D3 actions change with transformation but clinical data regarding vitamin D responsiveness of established tumors is limited and inconclusive. Because breast cancer is heterogeneous, analysis of VDR actions in specific molecular subtypes of the disease may help to clarify the conflicting data. The expanded use of genomic, proteomic and metabolomic approaches on a diverse array of in vitro and in vivo model systems is clearly warranted to comprehensively understand the network of vitamin D regulated pathways in the context of breast cancer.

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1α,25 Dihydroxyvitamin D3 enhances cellular defences against UV-induced oxidative and other forms of DNA damage in skin

Cited by 68 publications

References 74 publications

Chemical excitation of electrons: A dark path to melanoma

Chemical excitation of electrons: A dark path to melanoma

Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure

The impact of vitamin D in breast cancer: genomics, pathways, metabolism

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