cholecalciferol and Melanoma

Ultraviolet (UV) light is absorbed by nucleic acids, proteins or other endogenous chromophores, such as porphyrins, flavins and melanin, triggering biological processes in skin cells. Both UV-induced mutations in melanocytes and changes in the immune microenvironment are understood to play a role in the development of cutaneous melanoma. The degree of UV-induced stress and the protection against this stress are influenced by both intracellular and intercellular molecular interactions. The present review summarizes the known major molecular biological changes induced by UV light in the skin that play a role in melanoma initiation and promotion. Nevertheless, cutaneous melanoma is not a homogenous disease, and the interaction of variable environmental exposure and different genetic susceptibility and other host factors lead to the formation of melanomas with different biological behavior and clinical characteristics. This review highlights the challenges in the understanding of how UV radiation contributes to the formation of cutaneous melanoma, and reviews the new results of photobiology and their link to tumor genetics and tumor immunology with potential implications on melanoma prevention and therapeutic strategies. The information presented here is expected to add clarity to ongoing research efforts in this field to aid the development of novel strategies to prevent and treat melanoma.

Topics: Animals; Cholecalciferol; DNA Damage; Humans; Melanins; Melanoma; Melanoma, Cutaneous Malignant; Reactive Oxygen Species; Skin; Skin Neoplasms; Ultraviolet Rays

Vitamin D3 deficiency is rampant which may contribute to increased risk of many diseases including cancer, cardiovascular disease and autoimmune disorders. Genomic activity of the active metabolite 1,25-dihydroxyvitamin D (1,25D) mediates most vitamin D3's actions and many gene targets of 1,25D have been characterized. As the importance of non-coding RNAs has emerged, the ability of vitamin D3via 1,25D to regulate microRNAs (miRNAs) has been demonstrated in several cancer cell lines, patient tissue and sera. In vitamin D3 intervention patient trials, significant differences in miRNAs are observed between treatment groups and/or between baseline and followup. In patient sera from population studies, specific miRNA differences associate with serum levels of 25D. The findings thus far indicate that dietary vitamin D3 in patients and 1,25D in vitro not only regulate specific miRNA(s), but may also globally upregulate miRNA levels. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Topics: Breast Neoplasms; Calcitriol; Cholecalciferol; Colonic Neoplasms; Female; Humans; Leukemia; Male; Melanoma; MicroRNAs; Neoplasms; Prostatic Neoplasms

1,25-dihydroxyvitamin D3[1,25(OH)2D3] is a well-known potent regulator of cell growth and differentiation and there is recent evidence of an effect on cell death, tumour invasion and angiogenesis, which makes it a candidate agent for cancer regulation. The classical synthetic pathway of 1,25(OH)2D3 involves 25- and 1 alpha-hydroxylation of vitamin D3, in the liver and kidney, respectively, of absorbed or skin-synthesized vitamin D3. There is recent focus on the importance in growth control of local metabolism of 1,25(OH)2D3, which is a function of local tissue synthetic hydroxylases and particularly the principal catabolizing enzyme, 24-hydroxylase. The classical signalling pathway of 1,25(OH)2D3 employs the vitamin D nuclear receptor (VDR), which is a transcription factor for 1,25(OH)2D3 target genes. Effects of this pathway include inhibition of cellular growth and invasion. Cytoplasmic signalling pathways are increasingly being recognized, which similarly may regulate growth and differentiation but also apoptosis. 1,25(OH)2D3 has a major inhibitory effect on the G1/S checkpoint of the cell cycle by upregulating the cyclin dependent kinase inhibitors p27 and p21, and by inhibiting cyclin D1. Indirect mechanisms include upregulation of transforming growth factor-beta and downregulation of the epidermal growth factor receptor. 1,25(OH)2D3 may induce apoptosis either indirectly through effects on the insulin-like growth receptor and tumour necrosis factor-alpha or more directly via the Bcl-2 family system, the ceramide pathway, the death receptors (e.g. Fas) and the stress-activated protein kinase pathways (Jun N terminal kinase and p38). Inhibition of tumour invasion and metastasis potential has been demonstrated and mechanisms include inhibition of serine proteinases, metalloproteinases and angiogenesis. The lines of evidence for an effect of vitamin D3 in systemic cancer are the laboratory demonstration of relevant effects on cellular growth, differentiation, apoptosis, malignant cell invasion and metastasis; epidemiological findings of an association of the occurrence and outcome of cancers with derangements of vitamin D3/1,25(OH)2D3 and the association of functional polymorphisms of the VDR with the occurrence of certain cancers. In addition, vitamin D3 analogues are being developed as cancer chemotherapy agents. There is accumulating evidence that the vitamin D3/1,25(OH)2D3/VDR axis is similarly important in malignant melanoma (MM). MM cells express

Topics: Breast Neoplasms; Cell Differentiation; Cell Division; Cholecalciferol; Colonic Neoplasms; Female; Humans; Male; Melanoma; Polymorphism, Genetic; Prostatic Neoplasms; Receptors, Calcitriol; Signal Transduction; Skin; Skin Neoplasms; Vitamin D

Topics: Cholecalciferol; DNA Repair; Eye; Female; Humans; Male; Melanoma; Neoplasms, Radiation-Induced; Skin; Skin Aging; Skin Neoplasms; Sunburn; Sunlight; Ultraviolet Rays

Topics: Animals; Butyrates; Butyric Acid; Cell Division; Cell Line; Cell Transformation, Neoplastic; Cholecalciferol; Cyclic AMP; Humans; Melanoma; Protein Kinases; Retinoids; Teratoma; Tretinoin; Vitamin A

In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer (NMSC) and melanoma, we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a randomized placebo-controlled trial.. Postmenopausal women age 50 to 79 years (N = 36,282) enrolled onto the Women's Health Initiative (WHI) calcium/vitamin D clinical trial were randomly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 (CaD) daily or placebo for a mean follow-up period of 7.0 years. NMSC and melanoma skin cancers were ascertained by annual self-report; melanoma skin cancers underwent physician adjudication.. Neither incident NMSC nor melanoma rates differed between treatment (hazard ratio [HR], 1.02; 95% CI, 0.95 to 1.07) and placebo groups (HR, 0.86; 95% CI, 0.64 to 1.16). In subgroup analyses, women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo (HR, 0.43; 95% CI, 0.21 to 0.90; P(interaction) = .038), which was not observed in women without history of NMSC.. Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma. However, in women with history of NMSC, CaD supplementation reduced melanoma risk, suggesting a potential role for calcium and vitamin D supplements in this high-risk group. Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation.

Topics: Aged; Calcium, Dietary; Cholecalciferol; Confounding Factors, Epidemiologic; Dietary Supplements; Female; Follow-Up Studies; Humans; Incidence; Kaplan-Meier Estimate; Melanoma; Middle Aged; Odds Ratio; Postmenopause; Research Design; Risk Assessment; Risk Factors; Skin Neoplasms; Treatment Outcome; United States; Vitamin D; Women's Health

Proton beam irradiation promises therapeutic utility in the management of uveal melanoma. Calcitriol (1,25(OH)₂D₃)-the biologically active metabolite of vitamin D₃-and its precursor, calcidiol (25(OH)D₃), exert pleiotropic effects on melanoma cells. The aim of the study was to evaluate the effect of both calcitriol and calcidiol on melanoma cell proliferation and their response to proton beam irradiation. Three melanoma cell lines (human SKMEL-188 and hamster BHM Ma and BHM Ab), pre-treated with 1,25(OH)₂D₃ or 25(OH)D₃ at graded concentrations (0, 10, 100 nM), were irradiated with 0⁻5 Gy and then cultured in vitro. Growth curves were determined by counting the cell number every 24 h up to 120 h, which was used to calculate surviving fractions. The obtained survival curves were analysed using two standard models: linear-quadratic and multi-target single hit. Calcitriol inhibited human melanoma proliferation at 10 nM, while only calcidiol inhibited proliferation of hamster lines at 10 and 100 nM doses. Treatment with either 1,25(OH)₂D₃ or 25(OH)D₃ radio sensitized melanoma cells to low doses of proton beam radiation. The strength of the effect increased with the concentration of vitamin D₃. Our data suggest that vitamin D₃ may be an adjuvant that modifies proton beam efficiency during melanoma therapy.

Topics: Animals; Calcifediol; Calcitriol; Cell Line, Tumor; Cell Proliferation; Cholecalciferol; Cricetinae; Humans; Melanoma; Proton Therapy

Topics: Administration, Cutaneous; Adrenal Cortex Hormones; Antirheumatic Agents; Arthritis, Psoriatic; Back Pain; Biopsy; Cholecalciferol; Dendritic Cells; Female; Humans; Immunohistochemistry; Melanoma; Melanoma, Cutaneous Malignant; Methotrexate; Middle Aged; Ointments; PUVA Therapy; Retinoids; Severity of Illness Index; Skin Neoplasms

In the present study, we investigated the role of the transcription factor RUNX2 in melanomagenesis. We demonstrated that the expression of transcriptionally active RUNX2 was increased in melanoma cell lines as compared with human melanocytes. Using a melanoma tissue microarray, we showed that RUNX2 levels were higher in melanoma cells as compared with nevic melanocytes. RUNX2 knockdown in melanoma cell lines significantly decreased Focal Adhesion Kinase expression, and inhibited their cell growth, migration and invasion ability. Finally, the pro-hormone cholecalciferol reduced RUNX2 transcriptional activity and decreased migration of melanoma cells, further suggesting a role of RUNX2 in melanoma cell migration.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Cholecalciferol; Core Binding Factor Alpha 1 Subunit; Focal Adhesion Kinase 1; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Matrix Metalloproteinase 13; Melanoma; Neoplasm Invasiveness; Promoter Regions, Genetic; RNA Interference; Signal Transduction; Skin Neoplasms; Tissue Array Analysis; Transcription, Genetic; Transfection; Up-Regulation

The effects of six lipophilic vitamins: tretinoin (ATRA), vitamin D(3) (VD(3)), VE, VK(1), VK(3), and VK(5) on cell proliferation and apoptosis in human A375 melanoma cells were investigated. VD(3), VK(3), and VK(5) were found to inhibit cell proliferation significantly at concentration ranges of 10-100 μmol/L (p<0.01), while the other vitamins did not show inhibitory effects at 100 μmol/L. VK(3) and VK(5) showed the strongest effects with IC(50) values of less than 10 μmol/L. Dacarbazine slightly inhibited the proliferation of A375 cells at a concentration range of 25-100 μmol/L, but the effects were not statistically significant. VK(3) and VK(5) increased annexin-V positive apoptotic cells, as well as activating caspase-3, in A375 cells. Our findings showed that VD(3), VK(3,) and VK(5) inhibited the growth of dacarbazine resistant human melanoma cells, while ATRA, VE, and VK(1) had little effect on the cell growth. The effects of VK(3) and VK(5) were observed at concentrations lower than 10 μmol/L, which are suggested to have resulted from apoptosis-induction in the melanoma cells.

Topics: Annexin A5; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cholecalciferol; Dacarbazine; Drug Resistance, Neoplasm; Humans; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Melanoma; Tretinoin; Vitamin K; Vitamins

To define the interaction of novel secosteroids produced by the action of cytochrome P450scc with vitamin D receptor (VDR), we used a human melanoma line overexpressing VDR fused with enhanced green fluorescent protein (EGFP) and tested the ligand induced translocation of VDR from the cytoplasm to the nucleus. Hydroxyderivatives of vitamin D(3) with a full length (D(3)) side chain and hydroxy-secosteroids with a shortened side chain (pD) stimulated VDR translocation and inhibited proliferation, however, with different potencies. In general the D(3) were more potent than pD analogues. Molecular modeling of the binding of the secosteroids to the VDR genomic binding pocket (G-pocket) correlated well with the experimental data for VDR translocation. In contrast, docking scores for the non-genomic binding site of the VDR were poor. In conclusion, both the length of the side chain and the number and position of hydroxyl groups affect the activation of VDR by novel secosteroids.

Topics: Cell Nucleus; Cell Proliferation; Cholecalciferol; Cholesterol Side-Chain Cleavage Enzyme; Computer Simulation; Epidermal Cells; Humans; Keratinocytes; Melanoma; Models, Molecular; Molecular Docking Simulation; Protein Binding; Protein Transport; Receptors, Calcitriol; Secosteroids

Topics: Adult; Child; Child, Preschool; Cholecalciferol; Humans; Infant; Melanoma; Skin Neoplasms; Sunburn; Sunscreening Agents

Melanoma is highly resistant to current modalities of therapy, with the extent of pigmentation playing an important role in therapeutic resistance. Nuclear factor-κB (NF-κB) is constitutively activated in melanoma and can serve as a molecular target for cancer therapy and steroid/secosteroid action.. Cultured melanoma cells were used for mechanistic studies on NF-κB activity, utilising immunofluorescence, western blotting, EMSA, ELISA, gene reporter, and estimated DNA synthesis assays. Formalin-fixed, paraffin-embedded specimens from melanoma patients were used for immunocytochemical analysis of NF-κB activity in situ.. Novel 20-hydroxyvitamin (20(OH)D(3)) and classical 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) secosteroids inhibited melanoma cell proliferation. Active forms of vitamin D were found to inhibit NF-κB activity in nonpigmented cells, while having no effect on pigmented cells. Treatment of nonpigmented cells with vitamin D3 derivatives inhibited NF-κB DNA binding and NF-κB-dependent reporter assays, as well as inhibited the nuclear translocation of the p65 NF-κB subunit and its accumulation in the cytoplasm. Moreover, analysis of biopsies of melanoma patients showed that nonpigmented and slightly pigmented melanomas displayed higher nuclear NF-κB p65 expression than highly pigmented melanomas.. Classical 1,25(OH)(2)D(3) and novel 20(OH)D(3) hydroxyderivatives of vitamin D3 can target NF-κB and regulate melanoma progression in nonpigmented melanoma cells. Melanin pigmentation is associated with the resistance of melanomas to 20(OH)D(3) and 1,25(OH)(2)D(3) treatment.

Topics: Cell Division; Cell Line, Tumor; Cholecalciferol; Humans; Melanoma; NF-kappa B

Topics: Biomarkers; Cholecalciferol; Dietary Supplements; Evidence-Based Medicine; Humans; Melanoma; Neoplasm Staging; Risk Assessment; Skin Neoplasms; Survival Rate; Time Factors; Treatment Outcome; Up-Regulation

Cutaneous malignant melanoma (CMM) has been increasing at a steady exponential rate in fair-skinned, indoor workers since before 1940. A paradox exists between indoor and outdoor workers because indoor workers get three to nine times less solar UV (290-400 nm) exposure than outdoor workers get, yet only indoor workers have an increasing incidence of CMM. Thus, another "factor(s)" is/are involved that increases the CMM risk for indoor workers. We hypothesize that one factor involves indoor exposures to UVA (321-400 nm) passing through windows, which can cause mutations and can break down vitamin D(3) formed after outdoor UVB (290-320 nm) exposure, and the other factor involves low levels of cutaneous vitamin D(3). After vitamin D(3) forms, melanoma cells can convert it to the hormone, 1,25-dihydroxyvitamin D(3), or calcitriol, which causes growth inhibition and apoptotic cell death in vitro and in vivo. We measured the outdoor and indoor solar irradiances and found indoor solar UVA irradiances represent about 25% (or 5-10 W/m(2)) of the outdoor irradiances and are about 60 times greater than fluorescent light irradiances. We calculated the outdoor and indoor UV contributions toward different biological endpoints by weighting the emission spectra by the action spectra: erythema, squamous cell carcinoma, melanoma (fish), and previtamin D(3). Furthermore, we found production of previtamin D(3) only occurs outside where there is enough UVB. We agree that intense, intermittent outdoor UV overexposures and sunburns initiate CMM; we now propose that increased UVA exposures and inadequately maintained cutaneous levels of vitamin D(3) promotes CMM.

Topics: Cholecalciferol; Humans; Incidence; Melanoma; Skin; Skin Neoplasms; Ultraviolet Rays

Topics: Animals; Catechol Oxidase; Cell Line; Cholecalciferol; Cholesterol; Detergents; Ergocalciferols; Melanins; Melanocytes; Melanoma; Mice; Solubility; Spectrophotometry; Time Factors; Tritium