Beneficial Regulation of Cellular Oxidative Stress Effects, and Expression of Inflammatory, Angiogenic, and the Extracellular Matrix Remodeling Proteins by 1α,25-Dihydroxyvitamin D3 in a Melanoma Cell Line

Abstract

The causes of cancer include the cellular accumulation reactive oxygen species (ROS), which overrides the cellular antioxidants such as superoxide dismutase, from intrinsic aging, genetics, and exposure to environmental pollutants and ultraviolet (UV) radiation. The ROS damage biomolecules such as DNA (including p53 gene), RNA, and lipids, and activate inflammatory, angiogenic, and extracellular matrix (ECM) remodeling proteins; which collectively facilitate carcinogenesis. The 1α,25-dihydroxyvitamin D3 (Vitamin D) has anti-carcinogenic potential from its antioxidant, anti-inflammatory, and endocrine properties. We examined the anti-carcinogenic mechanism of vitamin D through the beneficial regulation of oxidative stress effects (oxidative DNA/RNA damage, superoxide dismutase expression, membrane damage, and p53 promoter activity), and expression (at the protein, mRNA and/or promoter levels) of inflammatory mediators (interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α)), angiogenic mediators (transforming growth factor-β (TGF-β), and vascular endothelial growth factor (VEGF)), and the ECM remodeling proteins (matrix metalloproteinases (MMP)-1 and MMP-2) by vitamin D in melanoma cells. Vitamin D inhibited oxidative DNA/RNA damage and membrane damage; and stimulated superoxide dismutase expression and p53 promoter activity in melanoma cells. It inhibited the expression of IL-1, TNF-α, TGF-β, VEGF, MMP-1 and MMP-2 by transcriptional or post-transcriptional mechanisms. We conclude that vitamin D is beneficial to melanoma cells through the inhibition of oxidative DNA/RNA damage, membrane damage, and the expression of inflammatory, angiogenic and ECM remodeling proteins; and the stimulation of superoxide dismutase expression and p53 promoter activity.

Anti-aging and anti-carcinogenic effects of 1α, 25-dihyroxyvitamin D3 on skin

“…Additionally, oxidative DNA damage has been seen to be accentuated by the depletion of glutathione in fibroblasts and melanoma cells [33] . Moreover, oxidative stress can also induce lipid peroxidation and cell membrane damage that leads to the leakage of intracellular proteins to the exterior [34,35] . Active substances with antioxidant properties such as VD, lutein, P. leucotomos extract and H. lupulus extract beneficially regulate oxidative stress in dermal fibroblasts and melanoma cells [31,[34][35][36][37][38][39] .…”

“…VD is photoprotective as it inhibits UV radiation-mediated oxidative DNA damage [34,35] , and induction of cellular skin defenses [40,41] . VD inhibits oxidative stress and tissue damage induced by exhaustive exercise and 2,2'-azino-di-(3-ethylbenzthiazoline sulphonate) oxidation in the presence of hydrogen peroxide and met-myoglobin [34,42] .…”

“…VD is photoprotective as it inhibits UV radiation-mediated oxidative DNA damage [34,35] , and induction of cellular skin defenses [40,41] . VD inhibits oxidative stress and tissue damage induced by exhaustive exercise and 2,2'-azino-di-(3-ethylbenzthiazoline sulphonate) oxidation in the presence of hydrogen peroxide and met-myoglobin [34,42] . It also inhibits oxidative DNA damage in non-irradiated or UV-radiated fibroblasts and melanoma cells; prevents membrane damage in UV-radiated fibroblasts and melanoma cells; decreases lipid peroxidation in non-irradiated and UVA-radiated fibroblasts; stimulates expression of superoxide dismutase in melanoma cells [34,35] [Figure 2].…”

“…VD inhibits oxidative stress and tissue damage induced by exhaustive exercise and 2,2'-azino-di-(3-ethylbenzthiazoline sulphonate) oxidation in the presence of hydrogen peroxide and met-myoglobin [34,42] . It also inhibits oxidative DNA damage in non-irradiated or UV-radiated fibroblasts and melanoma cells; prevents membrane damage in UV-radiated fibroblasts and melanoma cells; decreases lipid peroxidation in non-irradiated and UVA-radiated fibroblasts; stimulates expression of superoxide dismutase in melanoma cells [34,35] [Figure 2]. These data emerged from in vitro experiments in which different treatment conditions were evaluated: non-irradiated, UVA-irradiated, or UVB-irradiated human dermal fibroblasts, and melanoma cells (American Type Culture Collection, ATCC) were incubated for 24 h in the presence of different doses of VD (0, 0.02, 0.2, or 2 μM).…”

“…Cellular inflammation is also associated with increased production of angiogenic factors, such as vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and IL-8 [20,21] . VEGF binds to receptor tyrosine kinase to activate the mitogen-activated protein kinase (MAPK) pathway and thereby the activation of several transcription factors such as c-fos [34] . TGF-β binds to its receptors to activate SMADs that regulate the expression of cell cycle and the ECM [34] .…”