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.
Highlights
Carcinogenesis is associated with oxidative stress, inflammation, angiogenesis, and metastasis.The oxidative stress is from increased reactive oxygen species (ROS), which include hydroxyl radicals, superoxide, and hydrogen peroxide; and reduced counteracting antioxidants, which include superoxide dismutase, catalase, glutathione peroxidase, glutathione, ascorbate, α-tocopherol, and carotene
Relative to the control (100%), vitamin D at 0.0002, 0.002, 0.02, and 0.2 μM significantly inhibited oxidative damage to 81%, 68%, 61%, and 72% (p < 0.05) (Figure 1A); and significantly
Carcinogenesis is associated with increased oxidative stress, inflammation, angiogenesis, and inhibited matrix metalloproteinases (MMP)-2 protein levels to 65%, 46%,45%, and 33% of control (p < 0.05) (Figure 7A), in extracellular matrix (ECM) remodeling
Summary
Carcinogenesis is associated with oxidative stress, inflammation, angiogenesis, and metastasis. The oxidative stress is from increased reactive oxygen species (ROS), which include hydroxyl radicals, superoxide, and hydrogen peroxide; and reduced counteracting antioxidants, which include superoxide dismutase, catalase, glutathione peroxidase, glutathione, ascorbate, α-tocopherol, and carotene. The. ROS attack the DNA, proteins, and lipids directly. The oxidative damage to DNA and RNA includes the formation of 8-oxo-7, 8-dihydro-20 -deoxyguanosine (8-oxo-dG) or 8-oxo-7, 8-dihydro-20 -guanosine. Molecules 2020, 25, 1164; doi:10.3390/molecules25051164 www.mdpi.com/journal/molecules (8-oxo-G), which are increased in cancers [1,2,3,4,5,6,7,8,9,10,11,12]. The superoxide dismutases (SOD), including the mitochondrial MnSOD, are associated with gene mutations or altered expressions in cancers [4,6].
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