Skip to main content

Main menu

  • Home
  • Current Issue
  • Archive
  • Info for
    • Authors
    • Editorial Policies
    • Subscribers
    • Advertisers
    • Editorial Board
    • Special Issues 2025
  • Journal Metrics
  • Other Publications
    • In Vivo
    • Cancer Genomics & Proteomics
    • Cancer Diagnosis & Prognosis
  • More
    • IIAR
    • Conferences
    • 2008 Nobel Laureates
  • About Us
    • General Policy
    • Contact
  • Other Publications
    • Anticancer Research
    • In Vivo
    • Cancer Genomics & Proteomics

User menu

  • Register
  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Anticancer Research
  • Other Publications
    • Anticancer Research
    • In Vivo
    • Cancer Genomics & Proteomics
  • Register
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Anticancer Research

Advanced Search

  • Home
  • Current Issue
  • Archive
  • Info for
    • Authors
    • Editorial Policies
    • Subscribers
    • Advertisers
    • Editorial Board
    • Special Issues 2025
  • Journal Metrics
  • Other Publications
    • In Vivo
    • Cancer Genomics & Proteomics
    • Cancer Diagnosis & Prognosis
  • More
    • IIAR
    • Conferences
    • 2008 Nobel Laureates
  • About Us
    • General Policy
    • Contact
  • Visit us on Facebook
  • Follow us on Linkedin
Review ArticleReviewsR

Potential Molecular Mechanisms of the Anti-cancer Activity of Vitamin D

DOROTA SKRAJNOWSKA and BARBARA BOBROWSKA-KORCZAK
Anticancer Research July 2019, 39 (7) 3353-3363; DOI: https://doi.org/10.21873/anticanres.13478
DOROTA SKRAJNOWSKA
Department of Bromatology, Medical University of Warsaw, Warsaw, Poland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
BARBARA BOBROWSKA-KORCZAK
Department of Bromatology, Medical University of Warsaw, Warsaw, Poland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: barbara.bobrowska@wum.edu.pl
  • Article
  • Info & Metrics
  • PDF
Loading

Abstract

Vitamin D, or more precisely its active metabolite calcitriol (1,25-(OH)2D3), plays a fundamental role in bone metabolism and differentiation as well as in intestinal absorption of calcium and regulation of calcium-phosphate metabolism. Recent decades have brought about the discovery of the role of calcitriol in processes regulating cell differentiation, proliferation, angiogenesis and apoptosis. This creates the potential for numerous therapeutic applications of vitamin D in diseases associated with autoaggressive immune responses or in cancer. This study presents selected issues regarding current knowledge of the anti-cancer mechanisms of vitamin D.

  • Vitamin D
  • nVDR receptor
  • antitumor effect
  • review

The discovery that most tissues have receptors for vitamin D was a breakthrough in understanding its role in cancer development. A long-term vitamin D deficiency probably increases the risk of cancer (1-5). The hypothesis that vitamin D3 deficiency is linked to cancer development is supported by the results of experiments on animal models as well as epidemiological studies investigating the relationship between exposure to UVB radiation and cancer survival (6-8). Vitamin D protects the genome against the accumulation of mutations underlying neoplastic transformation and cancer progression. At the same time, owing to the anti-tumour activity of calcitriol and its analogues, these compounds can be used alone (promyelocytic leukaemia) or in synergy with other anticancer drugs, mainly cytostatics (9, 10). This means that the dose of cytostatics can be reduced, thereby reducing the risk of side effects following chemotherapy. For example, treatment with calcitriol in combination with carboplatin, dexamethasone or paclitaxel has been proven effective against both androgen-dependent and androgen-independent prostate cancer (10, 11). As in the case of prostate cancer (PCa), the therapeutic efficacy of calcitriol has also been confirmed in both hormone-dependent (oestrogen-receptor-positive) and oestrogen-receptor-negative breast cancer (12), as well as colorectal and head and neck cancer (13-17). The mechanism of the anti-neoplastic activity of vitamin D and its derivatives may vary depending on the type of cells and tissues. The excessive supply of calvium is itself considered by some researchers to be a PCa risk factor, and a low concentration of vitamin D may additionally increase the risk of prostate cancer by reducing production of 1,25-(OH)2D3. Moreover, a high concentration of Ca may inhibit the release of PTH (parathyroid hormone), which regulates the conversion of 25(OH)D3 to 1,25-(OH)2D3 in the kidneys (18).

Thus, there is a clear dependency between calcium supply and the concentration of 25(OH)D3 (19, 20). The mechanism of the biological activity of calcitriol is still quite difficult to explain, because the degree of inhibition of proliferation, apoptosis and cell cycle arrest depends on many different factors, primarily the degree of cell differentiation, the occurrence of growth factors, the dosage of vitamin D, and calcium concentrations in the intra- and extracellular environment.

Vitamin D – Cell Cycle Regulation

The growth and proliferation of hormone-dependent epithelial cells in health and disease depend on many intracellular signal transmission pathways. The signalling pathways may be activated by insulin-like growth factor 1 or 2 (IGF-1, IGF-2) or epidermal growth factor (EGF) and by pro-inflammatory cytokines such as tumour necrosis factor (TNF), interleukin-2 (IL-2) or granulocyte-macrophage colony-stimulating factor (GM-CSF). There are also pathways specific for tumours, called proliferative signalling pathways (21). The activation of transcription signalling pathways results in the modulation of numerous target genes which regulate proliferation of cells and genes influencing processes which mediate cell transformation in normal and proliferative tissues, such as inflammation, angiogenesis, cell mobility, and the ability to metastasize. These may lead to cell transformation and tumour formation. Vitamin D, primarily, influences calcium and phosphate balance, but in recent years a number of publications have highlighted its multi-faceted activity associated with the presence of the vitamin D receptor (VDR), including an anti-tumour effect (22). Although several mechanisms have been suggested to explain the inhibitory effect of 1,25(OH)2D3 on the cell cycle, no convincing data have been presented on the primary mechanism of the regulation of cell division. The most commonly mentioned mechanisms of cell cycle regulation by vitamin D are presented below.

In order for the cell to pass from phase G1 to phase S, in which DNA synthesis takes place, retinoblastoma (Rb) protein phosphorylation is required to activate transcription factors of the E2F family, which activate transcription of many genes, including cyclins E and A. Rb phosphorylation is catalysed by specific cyclin-dependent kinases (CDKs), whose activity is inhibited by p21 and p27 proteins. The complex of 1,25(OH)2D3 and VDR binds to the regulatory site in the promoter region of the p21 and p27 genes, intensifying their expression, which leads to inhibition of CDKs, lack of Rb phosphorylation, and cell-cycle arrest in the G1 phase (23, 24). The antiproliferative effect of vitamin D also involves modulation of intracellular kinase pathways (p38 MAPK – P38 mitogen-activated protein kinases, ERK – extracellular signal-regulated kinases, and PI3K – phosphoinositide 3-kinase) and repression of the proto-oncogene Myc, which plays the key role in cell proliferation (24).

1,25(OH)2D3 and its analogues are known to cause rapid and concentration-dependent (10−10−10−8 M) activation of phospholipase C, which is responsible for the hydrolysis of inositol lipids. This results in activation of protein kinase C (PKC) which plays an important regulatory in the control of gene expression; activates expression of the gene encoding Raf1 – a kinase of mitogen-activated kinase (MAPK). This is followed by an increase in the activity and phosphorylation of two members of the kinase family, MAPK-1 and MAPK-2, associated with regulation of the growth of many cells (25). In the context of long-term processes, PKC plays a significant role in cell differentiation, mobility and metastasis (2, 12).

The anti-proliferative effects of 25(OH)D3 correlate with the expression of endogenous 1-α-hydroxylase, whose activity is reduced in cancer cells compared to healthy prostate cells (5, 26, 27). The discovery of reduced activity of 1-α-hydroxylase in prostate cancer (PCa) epithelial cells provided an explanation for the locally reduced production of 1,25(OH)2D3, which results in the inhibition of cell differentiation and an increase in cancer invasiveness (27).

Another type of interaction of regulatory pathways caused by activation of the EGF (epidermal growth factor) receptor is the induction of other biological processes (apart from proliferation) in tumour transformation, such as inflammation, tumour angiogenesis, and infiltration, through stimulation of cyclooxygenase 2 (COX-2) and production of prostaglandin PGE2 (28, 29). It has been demonstrated that calcitriol may also inhibit the activity of cellular growth stimulators – prostaglandins. It has been shown that treatment of theprostate cancer cell line LNCaP with 1,25(OH)2D3 limits PGE2 synthesis (through inhibition of COX-2) and increases its inactivation (by stimulating prostaglandin dehydrogenase (15-PGDH), which transforms prostaglandins into ketone derivatives) (29).

Other mechanisms of cell cycle regulation by 1,25(OH)2D3 involve inhibition of mitogenic signals transmitted by growth factors such as EGF and stimulation of the pathways of transforming growth factor β (TGF-β) and insulin-like growth factor-binding proteins (IGF-BP), e.g. IGF-BP3 (30), as well as the aforementioned reduction of the expression of c-Myc gene, which plays a significant role in cell proliferation. In normal cells, the expression of c-Myc gene is correlated with an increase in the concentration of the c-Myc protein. This leads to metabolic disorders and tumour formation. Abnormal oncogene structure has been observed in many tumours.

Moreover, in cells exposed to calcitriol analogues, a reduction has been observed in the activity of ornithine decarboxylase, an enzyme necessary for DNA synthesis, as well as a decrease in the secretion of IL-6 (interleukin-2) and IL-8 (interleukin-8), which are known mitogens for keratinocytes (31).

One of the characteristic features of tumour cells is increased activity of telomerase. The enzyme is active in about 80-90% of all tumours and is responsible for the reconstruction of telomeres. It is a specialized DNA polymerase with reverse activity to that of transcriptase, which synthesises telomeric repetitions de novo (32, 33). The enzyme is composed of two key sub-units: a sub-unit consisting of an RNA chain (reverse transcriptase, RT) and the equally important sub-unit telomerase reverse transcriptase (TERT) (33-35). TERT has the ability to elongate telomeres in order to maintain the integrity of chromosomes, and in some sense regulates cell life span (34). It plays a significant role in proliferation, differentiation, carcinogenesis and ageing of cells (35). The RT and TERT sub-units together make up the enzyme core. Calcitriol and its analogues inhibit the high telomerase activity seen in human cancer cells by decreasing TERT mRNA expression. Induction of miR 498 gene by calcitriol is implicated in the down-regulation of TERT mRNA in some cancer cells (24).

Nuclear Vitamin D Receptor (nVDR)

Vitamin D initiates or suppresses the transcription of genes after binding to its receptor, VDR, which belongs to the nuclear receptor superfamily and acts as a ligand-activated transcription factor (1, 5). It is composed of the conserved N-terminal DNA-binding domain and an α-helical C-terminal ligand-binding domain. Binding of calcitriol to the ligand-binding domain causes heterodimerization of VDR with retinoid X receptor (RXR). This is necessary for binding to a DNA sequence known as the vitamin D response element (VDrE), located in the promoter region of the 1,25(OH)2D3 target genes (36, 37). These include the genes for amphiregulin – an epithelial growth factor stimulating the development of head and neck, and breast cancer (15, 38), the cell cycle inhibitor protein p21, apoptosis regulator protein bcl-2, and p53, a protein suppressing oncogenes that control cell growth, such as c-fos (39). Following binding to certain VDrE sequences and activating proteins, VDR acts as a transcription factor, inducing cell growth and proliferation as well as apoptosis (5). A significant discovery was the presence of VDR in cancerous cells, including breast cancer cells (40), which suggests that these cells may be susceptible to the effects of vitamin D. Advanced research is currently underway to introduce calcitriol and especially its analogues in the treatment of patients with breast, prostate, colorectal and head and neck cancer, as well as in combination therapy that is already used for acute promyelocytic leukaemia (9, 13, 15, 41-45). On the other hand, subtle allelic variations of the VDR gene located on chromosome 12 (12q13.1) are relatively common in the population (46). It has been demonstrated that polymorphisms in the VDR gene can play a significant role in the formation of cancers (47-49). Thus far, over 60 different polymorphisms localized in the promoter region, the region of exons 2-9, and the 3’UTR region have been detected. These can be single nucleotide polymorphisms (SNP) or functional polymorphisms, but also repeats (e.g. BsmI (G/A) (rs1544410), ApaI (G/T) (rs7975232), TaqI (T/C) (rs731236), Fok1 or Poly (A) in the 3’UTR region) (50). All changes in VDR can affect mRNA stability, and hence the translation of VDR mRNA. For example, the GG genotype of the ApaI (G/T) polymorphism influences the efficacy of chemotherapy in patients with non-small cell lung cancer (NSCLC). The authors of the study even suggested that the ApaI polymorphism in the VDR gene may prove to be a good marker for the use of individualized chemotherapy for NSCLC (51).

Thus, both normal and mutant VDR receptors are very important factors in the activity of vitamin D and its analogues in the process of tumorigenesis.

Vitamin D – Apoptosis Induction

Another possible pathway of the anti-tumour function of calcitriol is apoptosis induction, which has been demonstrated in tumour cells of the prostate, breast and large intestine (22, 52). However, the exact mechanism of this activity has not yet been identified. During apoptosis, the cell undergoes biochemical changes involving expression of specific genes (bax, bcl-2, TRPM-2/clusterin, cathepsin B) as well as morphological changes (cytoplasm condensation, DNA fragmentation or the formation of apoptotic bodies) (39, 53). Vitamin D treatment of colon cancer cells activates the expression of cystatins, endogenous inhibitors of cysteine proteases of the cathepsin family (54). Cathepsin B participates in the carcinogenesis process on many levels of tumour transformation, invasion and metastasis. Cathepsin B has been shown to enter into the cell nucleus and activate apoptosis (55). Most research studies have confirmed that the activity of cysteine endopeptidases can be measured as marker of tumour aggressiveness and their inhibitors as markers in diagnosis and monitoring of cancer therapy (56-58). In prostate epithelial cells, clusterin expression increases immediately after castration, reaching its maximum level in rat prostate cells 3-4 days after the procedure, which is associated with the beginning of mass cell death. At the same time, clusterin may be a marker of cell death and an apoptosis promoter. According to Zhu et al. (59), vitamin D may express its antitumoral effect by mediating the MEG3/clusterin signaling pathway. Proteins belonging to the bcl-2 family (B-cell CLL/lymphoma 2) play the key role in apoptosis regulation. Despite the similarity in their structure, different proteins in this family play opposite roles in the regulation of apoptosis. They may block apoptotic signals or cause an increase in the permeability of the external mitochondrial membrane to release of cytochrome c and activate caspases and cell death (60-62). Moreover, in the early stages of carcinogenesis, over-expression of protein bcl-2 protects cells with lethal mutations and contributes to genetic destabilization, a characteristic of tumours (62). The reduced efficiency of apoptosis in tumour cells may also be linked with mutations in the bax gene, one of the main effectors of p53-induced apoptosis (63). The co-dependency between the occurrence of TP53 gene mutations in cancers and disordered balance of the expression of bcl-2-bax is very often observed (64). Calcitriol has been found to decrease Bcl-2 expression in breast cancer cell lines (65). Ohnishi et al. have shown that vitamin D-induced cell-cycle arrest is mediated by inhibition of several key proteins which regulate the G1/S phase and by up-regulating TP53 expression (66).

Vitamin D – Inhibition of Invasiveness and Metastasis of Tumours

The colonization of tissues by tumour cells does not seem to be accidental. Tumour cells show some preferences for settling in a given organ (67). This probably takes place due to chemotaxis of tumour cells in connection with the level of cytokines produced by the cells, due to exceptionally favourable environmental conditions in the organ or to selective adhesion of tumour cells into the endothelial cells of the vessels in the organ. The over-expression of some integrins suggests that integrins are the main molecules involved in selective adhesion (68). In vivo research on animal models of prostate and bladder tumours has shown that 1,25(OH)2D3 reduces the invasiveness of tumours (69-71). Suggested mechanisms of the ‘anti-invasive’ function of vitamin D include inhibition of metalloproteinase and serine protease activity and increase E-cadherin expression, as well as reduction of the expression of integrins a6 and b4. E-cadherin belongs to the superfamily of calcium-dependent adhesion molecules. Changes in the expression and regulation of these proteins are strictly linked to tumour invasiveness. The loss of E-cadherin activity has been correlated with the clinical level of prostate cancer malignancy and the capacity to metastasize, as well as with poor overall survival of patients (72-74).

Vitamin D – Angiogenesis Inhibition

Another anti-tumour mechanism that has been described for 1,25(OH)2D3 is the inhibition of angiogenesis, e.g. in prostate cancer, both directly through the impact of tumour endothelial cells and indirectly through a reduction in the amount of COX-2-generated prostaglandin E2 (PGE2) (24, 31). One of the factors which induce angiogenesis is IL-8. The main functions of IL-8 are chemotactic attraction of neutrophils to the site of inflammation and stimulation of their bactericidal properties. Moreover, IL-8 plays a crucial role as an agent stimulating the formation of new blood vessels. In prostate cancer cells, 1,25(OH)2D3 has been shown to inhibit the activation of IL-8 gene transcription, most likely through interaction with the p65 subunit of nuclear factor kB (NF-kB). Other mechanisms of action of calcitriol through VDR include suppression of the expression of vascular endothelial growth factor (VEGF), angiopoietin 1 and platelet-derived growth factor (PDGF) and transcriptional repression of hypoxia-inducible factor 1 alpha (HIF1α) (75).

It is also worth noting that the presence of a physiological concentration of calcitriol is essential for a normal T lymphocyte-dependent immune response, which has been shown to depend on the presence of VDR (increased risk of infectious diseases with vitamin D insufficiency) (76).

Inhibition of Hedgehog (Hh) Signaling by Vitamin D

The Hh signaling begins with the attachment of the Hh peptide to the Patched (Ptch) receptor. The free form of Ptch inhibits Smoothened (Smo) protein. However, after Hh is attached, activation of Smo occurs, which induces the transport of GLI proteins to the cell nucleus followed by attachment to DNA and induction of transcription of target genes (77, 78). Deregulation of Hh signaling can lead both to stimulation and progression of cancer (79, 80). Four different types of human cancer, related to the Hh pathway, have been described: basal cell carcinoma, medulloblastoma, rhabdomyosarcoma and meningiomas (81). These can occur via mutations in the genes encoding components of the pathway (e.g., PTH1, CLI1, HIP or SFRP1) or by excess production of the Hh ligand by the tumor or stromal cells (80, 81). The drugs blocking the Hh pathway are relatively new in oncological medicine (82, 83). The first human inhibitor of Hh signaling, GDC- 0449, is now in clinical trials for at least 8 human cancers, and several other Hh inhibitors are in varying stages of clinical development. As early as in 2006, the inhibition of Hh signaling by vitamin D in vitro was described (84). The effect of Hh signaling on the growth of basal cell carcinoma (BCC) is particularly well documented (82, 85). Tang et al. (82) claimed that Vitamin D inhibits both Hh proliferation and signaling, on the basis of mRNA expression of the Hh GLI1 target gene. Moreover, it was emphasized that this effect was independent of the VDR receptor. Abert et al. (86) have shown that in Ptch mutant mice with basal cell carcinoma and in BCC cell lines, both Vitamin D and its active metabolite calcitriol (1,25(OH)2D3) exhibit an anticancer effect, mainly, by inhibiting Hh signaling.

Interaction of p53 and VDR Signaling

The p53 protein protects cells against changes in the genome due to DNA damage by inducing apoptosis, halting cell cycle progression or cellular aging (87). This protein undergoes inactivation in over 50% of cancer cases because of increased proteasomal degradation, or the presence of inactivating checkpoint mutations in its gene (88). This results, among other, in the formation of a transcriptionally inactive protein, hyperproduction of the mutant p53 protein or disturbance of p53 regulation by the chief negative regulators in the cell (by way of overexpression of binding factors – MDM2 and MDM4 (murine double minute 2 and 4) and the inhibition of transcription activity of the p53 protein (mainly MDM4) (89-92). Mutated p53 not only loses its tumor suppressor activity, but can also acquire oncogenic functions which are defined as gain-of-function (GOF) (93, 94). The introduction of the TP53 gene allele with null mutation to the stem cells of mice by way of homologous recombination, resulted in a spontaneous development of cancer in 75% of mice with the p53 phenotype (−/−) before they were 6 months old (95). On the other hand, the introduction of the gene encoding the wild type p53 (wtp53) to the cell line of mouse myeloid leukemia, devoid of the active p53 protein, resulted in a drastic reduction of cell viability and of apoptosis markers including chromatin condensation, nucleus fragmentation and DNA fragmentation (96).

Thus, restoration of the tumor suppressor function of the p53 protein in cancer cells could lead to cancer remission (97). Attempts have been made to design non-protein low-molecular mass inhibitors of MDM2-p53 interaction, and also of MDM4-p53, that will reactivate p53 and will have potential of being anticancer drugs (98), such as for example actinomycin D (99).

Vitamin D and its analogs are also considered to be potential antineoplastic agents. The active form of vitamin D, 1,25(OH)2D3, is capable of initiating or terminating gene transcription after binding to VDR which belongs to the nuclear receptor superfamily and functions of a ligand-activated transcription factor. Maruyama et al. (100) have confirmed that expression of the VDR gene is directly regulated by p53 protein. Overexpression of VDR increased the response to vitamin D treatment and inhibited the growth of colon cancer. The VDR gene is a transcription target of wtp53 and also of p63 and p73 (100-103). It is particularly interesting, that VDR is increased in several types of cancer, including breast and ovarian cancer (104, 105). A mutated p53 can cause deregulation of the anticancer activity of the VDR pathway. Stambolsky et al. (106) have described the mechanism of mutp53 GOF (gain-of-function), based on the interaction between p53 and VDR. It was shown that VDR and mutp53 (and also wtp53) interact with each other and this interaction increases as a result of vitamin D3 supplementation (106). The existence of an interaction between mutp53 and the regulation of transcription by calcitriol is probably due to the fact that mutp53 is bound to chromosome regions containing VDRE elements, probably via binding to VDR. Moreover, mutp53 increases nuclear accumulation of VDR which in some cases correlates with tumor stage (107, 108). In order to inhibit apoptosis, high endogenous levels of mutp53 in cancer cells probably cooperate with vitamin D, which is additionally enhanced by supplementation. The mutp53-dependent antiapoptotic activity of vitamin D has also been observed in breast cancer MDA-MB-231 and ovarian cancer OVCAR3 cell lines (106, 109). Moreover, increased VDR nuclear accumulation due to the activity of mutp53 can occur even without the supply of calcitriol, indicating that the mutant p53 protein changes the conformation of the receptor in a way that imitates the activity of vitamin D. It has been emphasized that the increased nuclear accumulation of VDR is probably not the only explanation of the effect of mutp53 (106). In the case of transactivation, VDR recruits mutp53 to VDRE in target genes, whereas mutp53 increases VDR-dependent transcription, thus stimulating the recruitment of additional transcription co-activators such as p300 (p300/cyclic AMP-response-element binding protein). The conversion of the VDR pathway from proapoptotic to antiapoptotic can occur due to a mutation in p53 GOF, at least in the cell lines which are protected by vitamin D. Undoubtedly, this discovery should be taken into account while deciding to apply therapies with vitamin D analogs for cancer. This means that apart from its well-documented proapoptotic activity, vitamin D can also have an antiapoptotic effect, and thus the VDR pathway can lead either to the patient's death or survival, depending on the presence of a TP53 mutation (106).

Vitamin D – Interaction of Photocarcinogenesis

Over 90% of vitamin D in the human body is produced in the skin in response to sun exposure. Human epithelial cells (keratinocytes) possess a complete system for the synthesis and metabolism of vitamin D. They have receptors for vitamin D (VDR) which are responsible for inducing gene expression. Both 25-hydroxylation and 1-hydroxylation lead to the formation of a biologically active form of vitamin D known as calcitriol (1,25(OH)2D3) and 24-hydroxylation leads to catabolism of vitamin D. Moreover, fibroblasts of the dermis possess a mechanism that allows the formation of 25(OH)D3, yet they do not have 1-hydroxylase and hence are unable to produce calcitriol (110). The application of vitamin D in dermatology is mainly due to its immunomodulatory properties, as well as its effect on the regulation of cell proliferation and differentiation. Vitamin D is formed in the epidermis and, together with calcium, it participates in the process of regeneration of the epidermal barrier (which is important for the treatment of various skin disorders such as psoriasis, photodermatoses, xeroderma pigmentosum and cancers) (111). Unfortunately, the increased incidence of skin cancers is largely the effect of increased exposure to ultraviolet radiation; UVB (which penetrates through the epidermis) and UVA (which penetrates into the dermis). The effects of excessive UV exposure include erythema, sunburns and dysfunction of Langerhans cells which are a part of the immune system of the skin. On the molecular level, exposure of DNA molecules to UV radiation leads to their damage, which in the absence of efficient repair systems can result in mutations and subsequently the initiation of neoplastic processes (112, 113). The potential anticancer activity of calcitriol in the case of malignant melanoma have been examined in many experimental and epidemiological studies, but contrary results have also been obtained (114-120). Sunburns in childhood (before the age of 15) are the most significant risk factor, regardless of the latitude of the children's locations (120). The systemic or local administration of 1,25(OH)2D3 immediately after excessive exposure to UV radiation was found to reduce sunburns in both humans and mice (121, 122). Besides, the presence of at least one actinic keratosis lesion also increases the risk of melanoma development (123). However, there is no unequivalent answer to the question concerning the relationship between the risk of melanoma and taking vitamin D either in the diet or in the form of supplements (124). Similarly, no relationship was found between the risk of developing melanoma and the concentration of vitamin D in serum (125). An attempt has been made to examine the effect of vitamin D used locally on the skin after exposure to UV radiation. It was found that tumor development was inhibited due to a strengthening of the repair mechanisms (126, 127). Makarova et al. (128) found that vitamin D synthetized in the skin by UVR protects the organism against oncogenic activity by inhibiting Hh signaling, whereas vitamin D taken in the diet does not exhibit such a protective mechanism, probably due to the rapid hydroxylation reaction accompanying oral intake (129).

UV radiation induces a number of changes in the skin by generating reactive oxygen species (ROS) and nitric oxide (NO) which can provoke DNA oxidative damage and lipid peroxidation. Promutagenic pyrimidine dimers and 8-hydroxy-2’deoxyguanosine are the major forms of DNA damage produced directly by UV radiation (122, 130-132). Vitamin D analogs were found to decrease the levels of thymine dimers which are formed after UV exposure (133) and the frequency of occurrence of oxidative and nitration DNA damage by reducing the production of NO and other toxic reactive forms of nitrogen (127, 133, 134). A decrease in DNA damage after exposure to UV radiation in the presence of 1,25(OH)2D3 has been observed in keratinocytes (127, 133), fibroblasts (135) and melanocytes (136). The protective activity of vitamin D against the sun's damaging effects to the skin also includes increase in the levels of p53 protein and metallothionein in the presence of calcitriol (127, 133, 134). A multifactorial effect of vitamin D to skin damage due to UV exposure is also related to the immune functions of the skin (among other things by its influence on maturation of the Langerhans cells presenting the antigen, NF-ĸB, T lymphocytes, IL-10, monocytes, macrophages) (122).

It seems that in the case of malignant melanoma the protective activity of sunrays through the synthesis of vitamin D is less important than its carcinogenic activity (regardless of the amount of time spent in the sun) (137, 138). The relationship between melanoma and sun radiation is very complicated and involves both the slow genome pathways (via the VDR receptor) and the rapid non-genome responses. Further investigations are required in this respect that would take into account not only the promising aspects of vitamin D anticancer effect, but its “dark” side as well.

Conclusion

On the basis of current data, it cannot be stated conclusively whether intake of vitamin D may offer protection against cancer. The presence of the VDR throughout the body and the effect of vitamin D on the cell cycle, apoptosis, angiogenesis, Hh signaling, interaction of p53 and photocarcinogenesis unquestionably suggest such a potential. However, further research is required, first to fully elucidate the mechanisms of action of this vitamin, and secondly to determine a specific dose and time of intake necessary to achieve an anticancer effect.

Acknowledgements

None declared.

Footnotes

  • Authors' Contributions

    Conception and drafting of the manuscript: Dorota Skrajnowska; Critical revision of the manuscript for important intellectual content: Barbara Bobrowska – Korczak. All Authors gave approval of the final version for submission.

  • Conflicts of Interest

    The Authors declare no conflict of interest.

  • Received March 15, 2019.
  • Revision received May 21, 2019.
  • Accepted May 23, 2019.
  • Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved

References

  1. ↵
    1. Yang S,
    2. Li A,
    3. Wang J,
    4. Liu J,
    5. Han Y,
    6. Zhang W,
    7. Li YC,
    8. Zhang H
    : Vitamin D receptor: A novel therapeutic target for kidney diseases. Curr Med Chem 25: 3256-3271, 2018. PMID: 29446731. DOI: 10.2174/0929867325666180214122352
    OpenUrlCrossRefPubMed
  2. ↵
    1. Zgaga L,
    2. Theodoratou E,
    3. Farrington SM,
    4. Din FVN,
    5. Ooi LY,
    6. Glodzik D,
    7. Johnston S,
    8. Tenesa A,
    9. Campbell H,
    10. Dunlop MG
    : Plasma Vitamin D concentration influences survival outcome after a diagnosis of colorectal cancer. J Clin Oncol 32: 2430-2439, 2014. PMID: 25002714. DOI: 10.1200/JCO.2013. 54.5947
    OpenUrlAbstract/FREE Full Text
    1. Lappe JM,
    2. Travers-Gustafson D,
    3. Davies KM,
    4. Recker RR,
    5. Heaney RP
    : Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 85: 1586-1591, 2007. PMID: 17556697. DOI: 10.1093/ajcn/ 85.6.1586
    OpenUrlAbstract/FREE Full Text
    1. Grant WB,
    2. Garland CF
    : The association of solar ultraviolet B (UVB) with reducing risk of cancer: multifactorial ecologic analysis of geographic variation in age-adjusted cancer mortality rates. Anticancer Res 26: 2687-2699, 2006. PMID: 16886679.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Fleet JC,
    2. DeSmet M,
    3. Johnson R,
    4. Li Y
    : Vitamin D and cancer: a review of molecular mechanisms. Biochem J 441: 61-76, 2012. PMID: 22168439. DOI: 10.1042/BJ20110744
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Welsh J
    : Vitamin D and breast cancer: insights from animal models. Am J Clin Nutr 80: 1721S-4S, 2004. PMID: 15585794. DOI: 10.1093/ajcn/80.6.1721S
    OpenUrlAbstract/FREE Full Text
    1. Grant WB,
    2. Garland CF,
    3. Holick MF
    : Comparisons of estimated economic burdens due to insufficient solar ultraviolet irradiance and vitamin D and excess solar UV irradiance for the United States. Photochem Photobiol 81: 1276-1286, 2005. PMID: 16159309. DOI: 10.1562/2005-01-24-RA-424
    OpenUrlCrossRefPubMed
  5. ↵
    1. Grant WB
    : Ecologic studies of solar UV-B radiation and cancer mortality rates. Recent Results Cancer Res Fortschritte Krebsforsch Progres Dans Rech Sur Cancer 164: 371-377, 2003. PMID: 12899536.
    OpenUrl
  6. ↵
    1. Gaschott T,
    2. Steinmeyer A,
    3. Steinhilber D,
    4. Stein J
    : ZK 156718, a low calcemic, antiproliferative, and prodifferentiating Vitamin D analog. Biochem Biophys Res Commun 290: 504-509, 2002. PMID: 11779200. DOI: 10.1006/bbrc.2001.6213
    OpenUrlCrossRefPubMed
  7. ↵
    1. Muindi JR,
    2. Peng Y,
    3. Potter DM,
    4. Hershberger PA,
    5. Tauch JS,
    6. Capozzoli MJ,
    7. Egorin MJ,
    8. Johnson CS,
    9. Trump DL
    : Pharmacokinetics of high-dose oral calcitriol: results from a phase 1 trial of calcitriol and paclitaxel. Clin Pharmacol Ther 72: 648-659, 2002. PMID: 12496746. DOI: 10.1067/mcp.2002.129305
    OpenUrlCrossRefPubMed
  8. ↵
    1. Johnson CS,
    2. Hershberger PA,
    3. Trump DL
    : Vitamin D-related therapies in prostate cancer. Cancer Metastasis Rev 21: 147-158, 2002. PMID: 12465754.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Welsh J,
    2. Wietzke JA,
    3. Zinser GM,
    4. Byrne B,
    5. Smith K,
    6. Narvaez CJ
    : Vitamin D-3 receptor as a target for breast cancer prevention. J Nutr 133: 2425S-2433S, 2003. PMID: 12840219. DOI: 10.1093/jn/133.7.2425S
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Lamprecht SA,
    2. Lipkin M
    : Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer 3: 601-614, 2003. PMID: 12894248. DOI: 10.1038/nrc1144
    OpenUrlCrossRefPubMed
    1. Díaz GD,
    2. Paraskeva C,
    3. Thomas MG,
    4. Binderup L,
    5. Hague A
    : Apoptosis is induced by the active metabolite of vitamin D3 and its analogue EB1089 in colorectal adenoma and carcinoma cells: possible implications for prevention and therapy. Cancer Res 60: 2304-2312, 2000. PMID: 10786699.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Akutsu N,
    2. Lin R,
    3. Bastien Y,
    4. Bestawros A,
    5. Enepekides DJ,
    6. Black MJ,
    7. White JH
    : Regulation of gene Expression by 1alpha,25-dihydroxyvitamin D3 and Its analog EB1089 under growth-inhibitory conditions in squamous carcinoma cells. Mol Endocrinol Baltim Md 15: 1127-1139, 2001. PMID: 11435613. DOI: 10.1210/mend.15.7.0655
    OpenUrl
    1. Ribiczey P,
    2. Papp B,
    3. Homolya L,
    4. Enyedi Á,
    5. Kovács T
    : Selective upregulation of the expression of plasma membrane calcium ATPase isoforms upon differentiation and 1,25(OH)2D3-vitamin treatment of colon cancer cells. Biochem Biophys Res Commun 464: 189-194, 2015. PMID: 26116539. DOI: 10.1016/j.bbrc.2015.06.113
    OpenUrlPubMed
  12. ↵
    1. Tidow H,
    2. Nissen P
    : Structural diversity of calmodulin binding to its target sites. FEBS J 280: 5551-5565, 2013. PMID: 23601118. DOI: 10.1111/febs.12296
    OpenUrlCrossRefPubMed
  13. ↵
    1. Lips P
    : Vitamin D physiology. Prog Biophys Mol Biol 92: 4-8, 2006. PMID: 16563471. DOI: 10.1016/j.pbiomolbio. 2006. 02.016
    OpenUrlCrossRefPubMed
  14. ↵
    1. Schwartz GG
    : Circulating vitamin D and risk of prostate cancer--letter. Cancer Epidemiol Biomarkers Prev 21: 246; author reply 247, 2012. PMID: 22045701. DOI: 10.1158/1055-9965.EPI-11-0910
    OpenUrlFREE Full Text
  15. ↵
    1. Skrajnowska D,
    2. Bobrowska-Korczak B,
    3. Tokarz A
    : Disorders of mechanisms of calcium metabolism control as potential risk factors of prostate cancer. Curr Med Chem 24: 4229-4244, 2017. PMID: 28901272. DOI: 10.2174/092986 7324666170913102834
    OpenUrlPubMed
  16. ↵
    1. Schalken JA
    : The androgen cascade in ageing men: Blessing or curse? Eur Urol Suppl 2: 8-12, 2003. DOI: 10.1016/j.eursup.2003.09.009
    OpenUrl
  17. ↵
    1. Beer TM,
    2. Myrthue A
    : Calcitriol in cancer treatment: from the lab to the clinic. Mol Cancer Ther 3: 373-381, 2004. PMID: 15026558.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Wade WN,
    2. Willingham MC,
    3. Koumenis C,
    4. Cramer SD
    : p27Kip1 is essential for the antiproliferative action of 1,25-dihydroxyvitamin D3 in primary, but not immortalized, mouse embryonic fibroblasts. J Biol Chem 277: 37301-37306, 2002. PMID: 12163488. DOI: 10.1074/jbc.M204162200
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Feldman D,
    2. Krishnan AV,
    3. Swami S,
    4. Giovannucci E,
    5. Feldman BJ
    : The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer 14: 342-357, 2014. PMID: 24705652. DOI: 10.1038/nrc3691
    OpenUrlCrossRefPubMed
  20. ↵
    1. Marcinkowska E
    : A run for a membrane vitamin D receptor. Biol Signals Recept 10: 341-349, 2001. PMID: 11721090. DOI: 10.1159/000046902
    OpenUrlCrossRefPubMed
  21. ↵
    1. Desprez PY,
    2. Poujol D,
    3. Falette N,
    4. Lefebvre MF,
    5. Saez S
    : 1,25-Dihydroxyvitamin D3 increases epidermal growth factor receptor gene expression in BT-20 breast carcinoma cells. Biochem Biophys Res Commun 176: 1-6, 1991. PMID: 1673338.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Roehrborn CG
    : Benign prostatic hyperplasia: An overview. Rev Urol 7: S3-S14, 2005. PMID: 16985902.
    OpenUrlPubMed
  23. ↵
    1. Li Y,
    2. Chinni SR,
    3. Sarkar FH
    : Selective growth regulatory and pro-apoptotic effects of DIM is mediated by AKT and NF-kappaB pathways in prostate cancer cells. Front Biosci J Virtual Libr 10: 236-243, 2005. PMID: 15574364.
    OpenUrl
  24. ↵
    1. Moreno J,
    2. Krishnan AV,
    3. Peehl DM,
    4. Feldman D
    : Mechanisms of vitamin D-mediated growth inhibition in prostate cancer cells: inhibition of the prostaglandin pathway. Anticancer Res 26: 2525-2530, 2006. PMID: 16886660.
    OpenUrlAbstract/FREE Full Text
  25. ↵
    1. Bouillon R,
    2. Eelen G,
    3. Verlinden L,
    4. Mathieu C,
    5. Carmeliet G,
    6. Verstuyf A
    : Vitamin D and cancer. J Steroid Biochem Mol Biol 102: 156-162, 2006. PMID: 17113979. DOI: 10.1016/j.jsbmb.2006.09.014
    OpenUrlCrossRefPubMed
  26. ↵
    1. Danilenko M,
    2. Studzinski GP
    : Enhancement by other compounds of the anti-cancer activity of vitamin D(3) and its analogs. Exp Cell Res 298: 339-358, 2004. PMID: 15265684. DOI: 10.1016/j.yexcr.2004.04.029
    OpenUrlCrossRefPubMed
  27. ↵
    1. Bibby MC
    : An introduction to telomeres and telomerase. Mol Biotechnol 24: 295-301, 2003. PMID: 12777695. DOI: 10.1385/MB:24:3:295
    OpenUrlPubMed
  28. ↵
    1. Blackburn EH
    : The end of the (DNA) line. Nat Struct Biol 7: 847-850, 2000. PMID: 11017190. DOI: 10.1038/79594
    OpenUrlCrossRefPubMed
  29. ↵
    1. Nicholls C,
    2. Li H,
    3. Wang J-Q,
    4. Liu J-P
    : Molecular regulation of telomerase activity in aging. Protein Cell 2: 726-738, 2011. PMID: 21976062. DOI: 10.1007/s13238-011-1093-3
    OpenUrlCrossRefPubMed
  30. ↵
    1. Cai Y,
    2. Ai Y,
    3. Zhao Q,
    4. Li J,
    5. Yang G,
    6. Gong P,
    7. Wang Q,
    8. Hou H,
    9. Zhang G,
    10. Li L,
    11. Yang J,
    12. Li H,
    13. Zheng J,
    14. Li S,
    15. Zhang X
    : Cloning and characterization of telomerase reverse transcriptase gene in Trichinella spiralis. Parasitol Res 110: 411-417, 2012. PMID: 21748355. DOI: 10.1007/s00436-011-2506-1
    OpenUrlPubMed
  31. ↵
    1. Prüfer K,
    2. Barsony J
    : Retinoid X receptor dominates the nuclear import and export of the unliganded vitamin D receptor. Mol Endocrinol Baltim Md 16: 1738-1751, 2002. PMID: 12145331. DOI: 10.1210/me.2001-0345
    OpenUrl
  32. ↵
    1. Haussler MR,
    2. Haussler CA,
    3. Jurutka PW,
    4. Thompson PD,
    5. Hsieh JC,
    6. Remus LS,
    7. Selznick SH,
    8. Whitfield GK
    : The vitamin D hormone and its nuclear receptor: molecular actions and disease states. J Endocrinol 154 Suppl: S57-73, 1997. PMID: 9379138.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Ryynänen J,
    2. Carlberg C
    : Primary 1,25-dihydroxyvitamin D3 response of the interleukin 8 gene cluster in human monocyte- and macrophage-like cells. PloS One 8: e78170, 2013. PMID: 24250750. DOI: 10.1371/journal.pone.0078170
    OpenUrlCrossRefPubMed
  34. ↵
    1. Hershberger PA,
    2. McGuire TF,
    3. Yu W-D,
    4. Zuhowski EG,
    5. Schellens JHM,
    6. Egorin MJ,
    7. Trump DL,
    8. Johnson CS
    : Cisplatin potentiates 1,25-dihydroxyvitamin D3-induced apoptosis in association with increased mitogen-activated protein kinase kinase kinase 1 (MEKK-1) expression. Mol Cancer Ther 1: 821-829, 2002. PMID: 12492115.
    OpenUrlAbstract/FREE Full Text
  35. ↵
    1. Ditsch N,
    2. Toth B,
    3. Mayr D,
    4. Lenhard M,
    5. Gallwas J,
    6. Weissenbacher T,
    7. Dannecker C,
    8. Friese K,
    9. Jeschke U
    : The association between vitamin D receptor expression and prolonged overall survival in breast cancer. J Histochem Cytochem 60: 121-129, 2012. PMID: 22108646. DOI: 10.1369/ 0022155411429155
    OpenUrlCrossRefPubMed
  36. ↵
    1. Berkovich L,
    2. Sintov AC,
    3. Ben-Shabat S
    : Inhibition of cancer growth and induction of apoptosis by BGP-13 and BGP-15, new calcipotriene-derived vitamin D3 analogs, in vitro and in vivo studies. Invest New Drugs 31: 247-255, 2013. PMID: 22661288. DOI: 10.1007/s10637-012-9839-1
    OpenUrlCrossRefPubMed
    1. Wu-Wong JR,
    2. Tian J,
    3. Goltzman D
    : Vitamin D analogs as therapeutic agents: a clinical study update. Curr Opin Investig Drugs Lond Engl 2000 5: 320-326, 2004. PMID: 15083599.
    OpenUrl
    1. Peehl DM,
    2. Krishnan AV,
    3. Feldman D
    : Pathways mediating the growth-inhibitory actions of vitamin D in prostate cancer. J Nutr 133: 2461S-2469S, 2003. PMID: 12840225. DOI: 10.1093/jn/133.7.2461S
    OpenUrlAbstract/FREE Full Text
    1. Zhang X,
    2. Giovannucci E
    : Calcium, vitamin D and colorectal cancer chemoprevention. Best Pract Res Clin Gastroenterol 25: 485-494, 2011. PMID: 22122765. DOI: 10.1016/j.bpg.2011.10.001
    OpenUrlCrossRefPubMed
  37. ↵
    1. Lin R,
    2. Nagai Y,
    3. Sladek R,
    4. Bastien Y,
    5. Ho J,
    6. Petrecca K,
    7. Sotiropoulou G,
    8. Diamandis EP,
    9. Hudson TJ,
    10. White JH
    : Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol Baltim Md 16: 1243-1256, 2002. PMID: 12040012. DOI: 10.1210/mend.16.6.0874
    OpenUrl
  38. ↵
    1. Koshiyama H,
    2. Sone T,
    3. Nakao K
    : Vitamin-D-receptor-gene polymorphism and bone loss. Lancet Lond Engl 345: 990-991, 1995. PMID: 7715321.
    OpenUrl
  39. ↵
    1. van den Bemd GJ,
    2. Pols HA,
    3. van Leeuwen JP
    : Anti-tumor effects of 1,25-dihydroxyvitamin D3 and vitamin D analogs. Curr Pharm Des 6: 717-732, 2000. PMID: 10828303.
    OpenUrlCrossRefPubMed
    1. Woloszynska-Read A,
    2. Johnson CS,
    3. Trump DL
    : Vitamin D and cancer: clinical aspects. Best Pract Res Clin Endocrinol Metab 25: 605-615, 2011. PMID: 21872802. DOI: 10.1016/j.beem.2011.06.006
    OpenUrlCrossRef
  40. ↵
    1. Plum LA,
    2. Prahl JM,
    3. Ma X,
    4. Sicinski RR,
    5. Gowlugari S,
    6. Clagett-Dame M,
    7. DeLuca HF
    : Biologically active noncalcemic analogs of 1alpha,25-dihydroxyvitamin D with an abbreviated side chain containing no hydroxyl. Proc Natl Acad Sci USA 101: 6900-6904, 2004. PMID: 15118084. DOI: 10.1073/pnas.0401656101
    OpenUrlAbstract/FREE Full Text
  41. ↵
    1. Gardiner EM,
    2. Esteban LM,
    3. Fong C,
    4. Allison SJ,
    5. Flanagan JL,
    6. Kouzmenko AP,
    7. Eisman JA
    : Vitamin D receptor B1 and exon 1d: functional and evolutionary analysis. J Steroid Biochem Mol Biol 89-90: 233-238, 2004. PMID: 15225777. DOI: 10.1016/j.jsbmb.2004.03.078
    OpenUrlCrossRefPubMed
  42. ↵
    1. Xiong L,
    2. Cheng J,
    3. Gao J,
    4. Wang J,
    5. Liu X,
    6. Wang L
    : Vitamin D receptor genetic variants are associated with chemotherapy response and prognosis in patients with advanced non-small-cell lung cancer. Clin Lung Cancer 14: 433-439, 2013. PMID: 23522953. DOI: 10.1016/j.cllc.2013.01.004
    OpenUrlPubMed
  43. ↵
    1. Elmore S
    : Apoptosis: a review of programmed cell death. Toxicol Pathol 35: 495-516, 2007. PMID: 17562483. DOI: 10.1080/01926230701320337
    OpenUrlCrossRefPubMed
  44. ↵
    1. Trump DL,
    2. Hershberger PA,
    3. Bernardi RJ,
    4. Ahmed S,
    5. Muindi J,
    6. Fakih M,
    7. Yu W-D,
    8. Johnson CS
    : Anti-tumor activity of calcitriol: pre-clinical and clinical studies. J Steroid Biochem Mol Biol 89-90: 519-526, 2004. PMID: 15225831. DOI: 10.1016/j.jsbmb.2004.03.068
    OpenUrl
  45. ↵
    1. Gonzalez-Suarez I,
    2. Redwood AB,
    3. Grotsky DA,
    4. Neumann MA,
    5. Cheng EH-Y,
    6. Stewart CL,
    7. Dusso A,
    8. Gonzalo S
    : A new pathway that regulates 53BP1 stability implicates cathepsin L and vitamin D in DNA repair. EMBO J 30: 3383-3396, 2011. PMID: 21750527. DOI: 10.1038/emboj.2011.225
    OpenUrlAbstract/FREE Full Text
  46. ↵
    1. Bröker LE,
    2. Kruyt FAE,
    3. Giaccone G
    : Cell death independent of caspases: a review. Clin Cancer Res 11: 3155-3162, 2005. PMID: 15867207. DOI: 10.1158/1078-0432.CCR-04-2223
    OpenUrlAbstract/FREE Full Text
  47. ↵
    1. Tokarzewicz A,
    2. Gorodkiewicz E
    : Proteases: significance, role and determination. CHEMIK 69: 81-88, 2015.
    OpenUrl
    1. Sinha AA,
    2. Quast BJ,
    3. Wilson MJ,
    4. Fernandes ET,
    5. Reddy PK,
    6. Ewing SL,
    7. Gleason DF
    : Prediction of pelvic lymph node metastasis by the ratio of cathepsin B to stefin A in patients with prostate carcinoma. Cancer 94: 3141-3149, 2002. PMID: 12115346. DOI: 10.1002/cncr.10604
    OpenUrlCrossRefPubMed
  48. ↵
    1. Levicar N,
    2. Strojnik T,
    3. Kos J,
    4. Dewey RA,
    5. Pilkington GJ,
    6. Lah TT
    : Lysosomal enzymes, cathepsins in brain tumour invasion. J Neurooncol 58: 21-32, 2002. PMID: 12160137.
    OpenUrlCrossRefPubMed
  49. ↵
    1. Zhu Y,
    2. Chen P,
    3. Gao Y,
    4. Ta ND,
    5. Zhang Y,
    6. Cai J,
    7. Zhao Y,
    8. Liu S,
    9. Zheng J
    : MEG3 activated by vitamin d inhibits colorectal cancer cells proliferation and migration via regulating clusterin. In: EBioMedicine, 2018. PMID: 29628342. DOI: 10.1016/j.ebiom.2018.03.032
  50. ↵
    1. Abramson JS,
    2. Shipp MA
    : Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. Blood 106: 1164-1174, 2005. PMID: 15855278. DOI: 10.1182/blood-2005-02-0687
    OpenUrlAbstract/FREE Full Text
    1. Pasqualucci L,
    2. Bhagat G,
    3. Jankovic M,
    4. Compagno M,
    5. Smith P,
    6. Muramatsu M,
    7. Honjo T,
    8. Morse HC,
    9. Nussenzweig MC,
    10. Dalla-Favera R
    : AID is required for germinal center-derived lymphomagenesis. Nat Genet 40: 108-112, 2008. PMID: 18066064. DOI: 10.1038/ng.2007.35
    OpenUrlCrossRefPubMed
  51. ↵
    1. Fulda S,
    2. Meyer E,
    3. Debatin K-M
    : Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression. Oncogene 21: 2283-2294, 2002. PMID: 11948412. DOI: 10.1038/sj.onc. 1205258
    OpenUrlCrossRefPubMed
  52. ↵
    1. Gómez-Navarro J,
    2. Arafat W,
    3. Xiang J
    : Gene therapy for carcinoma of the breast: Pro-apoptotic gene therapy. Breast Cancer Res 2: 32-44, 2000. PMID: 11250691. DOI: 10.1186/bcr27
    OpenUrlCrossRefPubMed
  53. ↵
    1. Müllauer L,
    2. Gruber P,
    3. Sebinger D,
    4. Buch J,
    5. Wohlfart S,
    6. Chott A
    : Mutations in apoptosis genes: a pathogenetic factor for human disease. Mutat Res 488: 211-231, 2001. PMID: 11397650.
    OpenUrlCrossRefPubMed
  54. ↵
    1. Chakraborti CK
    : Vitamin D as a promising anticancer agent. Indian J Pharmacol 43: 113-120, 2011. PMID: 21572642. DOI: 10.4103/0253-7613.77335
    OpenUrlPubMed
  55. ↵
    1. Ohnishi T,
    2. Takahashi A,
    3. Ohnishi K
    : Studies about space radiation promote new fields in radiation biology. J Radiat Res (Tokyo) 43 Suppl: S7-12, 2002. PMID: 12793723. DOI: 10.1269/jrr.43.s7
    OpenUrlCrossRefPubMed
  56. ↵
    1. Gassmann P,
    2. Enns A,
    3. Haier J
    : Role of tumor cell adhesion and migration in organ-specific metastasis formation. Onkologie 27: 577-582, 2004. PMID: 15591720. DOI: 10.1159/ 000081343
    OpenUrlCrossRefPubMed
  57. ↵
    1. Eble JA,
    2. Haier J
    : Integrins in cancer treatment. Curr Cancer Drug Targets 6: 89-105, 2006. PMID: 16529540.
    OpenUrlCrossRefPubMed
  58. ↵
    1. Hansen CM,
    2. Frandsen TL,
    3. Brünner N,
    4. Binderup L
    : 1 alpha,25-Dihydroxyvitamin D3 inhibits the invasive potential of human breast cancer cells in vitro. Clin Exp Metastasis 12: 195-202, 1994. PMID: 8194194.
    OpenUrlCrossRefPubMed
    1. Konety BR,
    2. Lavelle JP,
    3. Pirtskalaishvili G,
    4. Dhir R,
    5. Meyers SA,
    6. Nguyen TS,
    7. Hershberger P,
    8. Shurin MR,
    9. Johnson CS,
    10. Trump DL,
    11. Zeidel ML,
    12. Getzenberg RH
    : Effects of vitamin D (calcitriol) on transitional cell carcinoma of the bladder in vitro and in vivo. J Urol 165: 253-258, 2001. PMID: 11125420. DOI: 10.1097/00005392-200101000-00074
    OpenUrlCrossRefPubMed
  59. ↵
    1. Young MR,
    2. Ihm J,
    3. Lozano Y,
    4. Wright MA,
    5. Prechel MM
    : Treating tumor-bearing mice with vitamin D3 diminishes tumor-induced myelopoiesis and associated immunosuppression, and reduces tumor metastasis and recurrence. Cancer Immunol Immunother CII 41: 37-45, 1995. PMID: 7641218.
    OpenUrlPubMed
  60. ↵
    1. Prevarskaya N,
    2. Skryma R,
    3. Shuba Y
    : Calcium in tumour metastasis: new roles for known actors. Nat Rev Cancer 11: 609-618, 2011. PMID: 21779011. DOI: 10.1038/nrc3105
    OpenUrlCrossRefPubMed
    1. Cavallaro U,
    2. Schaffhauser B,
    3. Christofori G
    : Cadherins and the tumour progression: is it all in a switch? Cancer Lett 176: 123-128, 2002. PMID: 11804738.
    OpenUrlCrossRefPubMed
  61. ↵
    1. Morita N,
    2. Uemura H,
    3. Tsumatani K,
    4. Cho M,
    5. Hirao Y,
    6. Okajima E,
    7. Konishi N,
    8. Hiasa Y
    : E-cadherin and α-, β- and γ-catenin expression in prostate cancers: correlation with tumour invasion. Br J Cancer 79: 1879-1883, 1999. PMID: 10206308. DOI: 10.1038/sj.bjc.6690299
    OpenUrlCrossRefPubMed
  62. ↵
    1. Nabeshima Y,
    2. Imura H
    : alpha-Klotho: a regulator that integrates calcium homeostasis. Am J Nephrol 28: 455-464, 2008. PMID: 18160815. DOI: 10.1159/000112824
    OpenUrlCrossRefPubMed
  63. ↵
    1. Baeke F,
    2. Korf H,
    3. Overbergh L,
    4. van Etten E,
    5. Verstuyf A,
    6. Gysemans C,
    7. Mathieu C
    : Human T lymphocytes are direct targets of 1,25-dihydroxyvitamin D3 in the immune system. J Steroid Biochem Mol Biol 121: 221-227, 2010. PMID: 20302932. DOI: 10.1016/j.jsbmb.2010.03.037
    OpenUrlCrossRefPubMed
  64. ↵
    1. Goetz SC,
    2. Anderson KV
    : The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 11: 331-344, 2010. PMID: 20395968. DOI: 10.1038/nrg2774
    OpenUrlCrossRefPubMed
  65. ↵
    1. Haycraft CJ,
    2. Banizs B,
    3. Aydin-Son Y,
    4. Zhang Q,
    5. Michaud EJ,
    6. Yoder BK
    : Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 1, 2005. PMID: 16254602. DOI: 10.1371/journal.pgen.0010053
  66. ↵
    1. Jiang J,
    2. Hui C-C
    : Hedgehog signaling in development and cancer. Dev Cell 15: 801-812, 2008. PMID: 19081070. DOI: 10.1016/j.devcel.2008.11.010
    OpenUrlCrossRefPubMed
  67. ↵
    1. Nolan-Stevaux O,
    2. Lau J,
    3. Truitt ML,
    4. Chu GC,
    5. Hebrok M,
    6. Fernández-Zapico ME,
    7. Hanahan D
    : GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev 23: 24-36, 2009. PMID: 19136624. DOI: 10.1101/gad.1753809
    OpenUrlAbstract/FREE Full Text
  68. ↵
    1. Gu D,
    2. Xie J
    : Non-canonical Hh signaling in cancer – current understanding and future directions. Cancers 7: 1684-1698, 2015. PMID: 26343727. DOI: 10.3390/cancers7030857
    OpenUrlPubMed
  69. ↵
    1. Tang JY,
    2. Xiao TZ,
    3. Oda Y,
    4. Chang KS,
    5. Shpall E,
    6. Wu A,
    7. So P-L,
    8. Hebert J,
    9. Bikle D,
    10. Epstein EH
    : Vitamin D3 inhibits hedgehog signaling and proliferation in murine Basal cell carcinomas. Cancer Prev Res (Phila) 4: 744-751, 2011. PMID: 21436386. DOI: 10.1158/1940-6207.CAPR-10-0285
    OpenUrlAbstract/FREE Full Text
  70. ↵
    1. Frampton JE,
    2. Basset-Séguin N
    : Vismodegib: A review in advanced basal cell carcinoma. Drugs 78: 1145-1156, 2018. PMID: 30030732. DOI: 10.1007/s40265-018-0948-9
    OpenUrlPubMed
  71. ↵
    1. Bijlsma MF,
    2. Spek CA,
    3. Zivkovic D,
    4. van de Water S,
    5. Rezaee F,
    6. Peppelenbosch MP
    : Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLoS Biol 4, 2006. PMID: 16895439. DOI: 10.1371/journal.pbio.0040232
  72. ↵
    1. Von Hoff DD,
    2. LoRusso PM,
    3. Rudin CM,
    4. Reddy JC,
    5. Yauch RL,
    6. Tibes R,
    7. Weiss GJ,
    8. Borad MJ,
    9. Hann CL,
    10. Brahmer JR,
    11. Mackey HM,
    12. Lum BL,
    13. Darbonne WC,
    14. Marsters JC,
    15. de Sauvage FJ,
    16. Low JA
    : Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 361: 1164-1172, 2009. DOI: 10.1056/NEJMoa0905360
    OpenUrlCrossRefPubMed
  73. ↵
    1. Albert B,
    2. Hahn H
    : Interaction of hedgehog and vitamin D signaling pathways in basal cell carcinomas. Adv Exp Med Biol 810: 329-341, 2014. PMID: 25207374.
    OpenUrlPubMed
  74. ↵
    1. Meulmeester E,
    2. Jochemsen AG
    : p53: a guide to apoptosis. Curr Cancer Drug Targets 8: 87-97, 2008. PMID: 18336191.
    OpenUrlCrossRefPubMed
  75. ↵
    1. Yue X,
    2. Zhao Y,
    3. Xu Y,
    4. Zheng M,
    5. Feng Z,
    6. Hu W
    : Mutant p53 in cancer: Accumulation, gain-of-function, and therapy. J Mol Biol 429: 1595-1606, 2017. PMID: 28390900. DOI: 10.1016/j.jmb.2017.03.030
    OpenUrlCrossRefPubMed
  76. ↵
    1. Vousden KH,
    2. Lu X
    : Live or let die: the cell's response to p53. Nat Rev Cancer 2: 594-604, 2002. PMID: 12154352. DOI: 10.1038/nrc864
    OpenUrlCrossRefPubMed
    1. Bond GL,
    2. Hu W,
    3. Levine AJ
    : MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets 5: 3-8, 2005. PMID: 15720184.
    OpenUrlCrossRefPubMed
    1. Chène P
    : Inhibiting the p53–MDM2 interaction: an important target for cancer therapy. Nat Rev Cancer 3: 102-109, 2003. PMID: 12563309. DOI: 10.1038/nrc991
    OpenUrlCrossRefPubMed
  77. ↵
    1. Weisz L,
    2. Oren M,
    3. Rotter V
    : Transcription regulation by mutant p53. Oncogene 26: 2202-2211, 2007. PMID: 17401429. DOI: 10.1038/sj.onc.1210294
    OpenUrlCrossRefPubMed
  78. ↵
    1. Bossi G,
    2. Lapi E,
    3. Strano S,
    4. Rinaldo C,
    5. Blandino G,
    6. Sacchi A
    : Mutant p53 gain of function: reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression. Oncogene 25: 304-309, 2006. PMID: 16170357. DOI: 10.1038/sj.onc.1209026
    OpenUrlCrossRefPubMed
  79. ↵
    1. Weisz L,
    2. Zalcenstein A,
    3. Stambolsky P,
    4. Cohen Y,
    5. Goldfinger N,
    6. Oren M,
    7. Rotter V
    : Transactivation of the EGR1 gene contributes to mutant p53 gain of function. Cancer Res 64: 8318-8327, 2004. PMID: 15548700. DOI: 10.1158/0008-5472.CAN-04-1145
    OpenUrlAbstract/FREE Full Text
  80. ↵
    1. Donehower LA,
    2. Harvey M,
    3. Slagle BL,
    4. McArthur MJ,
    5. Montgomery CA,
    6. Butel JS,
    7. Bradley A
    : Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356: 215-221, 1992. PMID: 1552940. DOI: 10.1038/356215a0
    OpenUrlCrossRefPubMed
  81. ↵
    1. Yonish-Rouach E,
    2. Resnitzky D,
    3. Lotem J,
    4. Sachs L,
    5. Kimchi A,
    6. Oren M
    : Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 352: 345-347, 1991. PMID: 1852210. DOI: 10.1038/352345a0
    OpenUrlCrossRefPubMed
  82. ↵
    1. Gebow D,
    2. Miselis N,
    3. Liber HL
    : Homologous and nonhomologous recombination resulting in deletion: effects of p53 status, microhomology, and repetitive DNA length and orientation. Mol Cell Biol 20: 4028-4035, 2000. PMID: 10805745. DOI: 10.1128/mcb.20.11.4028-4035.2000
    OpenUrlAbstract/FREE Full Text
  83. ↵
    1. Vassilev LT
    : MDM2 inhibitors for cancer therapy. Trends Mol Med 13: 23-31, 2007. PMID: 17126603. DOI: 10.1016/j.molmed.2006.11.002
    OpenUrlCrossRefPubMed
  84. ↵
    1. Choong ML,
    2. Yang H,
    3. Lee MA,
    4. Lane DP
    : Specific activation of the p53 pathway by low dose actinomycin D: a new route to p53 based cyclotherapy. Cell Cycle Georget Tex 8: 2810-2818, 2009. PMID: 19657224. DOI: 10.4161/ cc.8.17.9503
    OpenUrl
  85. ↵
    1. Maruyama R,
    2. Toyota M,
    3. Suzuki H,
    4. Sasaki Y,
    5. Aoki F,
    6. Shinomura Y,
    7. Imai K,
    8. Tokino T
    : The functional relation of vitamin D receptor and p53 in cancer cells. Cancer Epidemiol Prevent Biomarkers 15: B133, 2006.
    OpenUrl
    1. Maruyama R,
    2. Aoki F,
    3. Toyota M,
    4. Sasaki Y,
    5. Akashi H,
    6. Mita H,
    7. Suzuki H,
    8. Akino K,
    9. Ohe-Toyota M,
    10. Maruyama Y,
    11. Tatsumi H,
    12. Imai K,
    13. Shinomura Y,
    14. Tokino T
    : Comparative genome analysis identifies the vitamin D receptor gene as a direct target of p53-mediated transcriptional activation. Cancer Res 66: 4574-4583, 2006. PMID: 16651407. DOI: 10.1158/0008-5472.CAN-05-2562
    OpenUrlAbstract/FREE Full Text
    1. Kommagani R,
    2. Caserta TM,
    3. Kadakia MP
    : Identification of vitamin D receptor as a target of p63. Oncogene 25: 3745-3751, 2006. PMID: 16462763. DOI: 10.1038/sj.onc.1209412
    OpenUrlCrossRefPubMed
  86. ↵
    1. Kommagani R,
    2. Payal V,
    3. Kadakia MP
    : Differential regulation of vitamin D receptor (VDR) by the p53 Family: p73-dependent induction of VDR upon DNA damage. J Biol Chem 282: 29847-29854, 2007. PMID: 17716971. DOI: 10.1074/jbc.M703641200
    OpenUrlAbstract/FREE Full Text
  87. ↵
    1. Friedrich M,
    2. Rafi L,
    3. Tilgen W,
    4. Schmidt W,
    5. Reichrath J
    : Expression of 1,25-dihydroxy vitamin D3 receptor in breast carcinoma. J Histochem Cytochem Off J Histochem Soc 46: 1335-1337, 1998. PMID: 9774633. DOI: 10.1177/0022155 49804601114
    OpenUrl
  88. ↵
    1. Friedrich M,
    2. Villena-Heinsen C,
    3. Tilgen W,
    4. Schmidt W,
    5. Reichrat J,
    6. Axt-Fliedner R
    : Vitamin D receptor (VDR) expression is not a prognostic factor in breast cancer. Anticancer Res 22: 1919-1924, 2002. PMID: 12168894.
    OpenUrlPubMed
  89. ↵
    1. Stambolsky P,
    2. Tabach Y,
    3. Fontemaggi G,
    4. Weisz L,
    5. Maor-Aloni R,
    6. Siegfried Z,
    7. Sigfried Z,
    8. Shiff I,
    9. Kogan I,
    10. Shay M,
    11. Kalo E,
    12. Blandino G,
    13. Simon I,
    14. Oren M,
    15. Rotter V
    : Modulation of the vitamin D3 response by cancer-associated mutant p53. Cancer Cell 17: 273-285, 2010. PMID: 20227041. DOI: 10.1016/j.ccr.2009.11.025
    OpenUrlCrossRefPubMed
  90. ↵
    1. Menezes RJ,
    2. Cheney RT,
    3. Husain A,
    4. Tretiakova M,
    5. Loewen G,
    6. Johnson CS,
    7. Jayaprakash V,
    8. Moysich KB,
    9. Salgia R,
    10. Reid ME
    : Vitamin D receptor expression in normal, premalignant, and malignant human lung tissue. Cancer Epidemiol Biomarkers Prev 17: 1104-1110, 2008. PMID: 18483332. DOI: 10.1158/1055-9965.EPI-07-2713
    OpenUrlAbstract/FREE Full Text
  91. ↵
    1. Sahin MO,
    2. Canda AE,
    3. Yorukoglu K,
    4. Mungan MU,
    5. Sade M,
    6. Kirkali Z
    : 1,25 Dihydroxyvitamin D(3) receptor expression in superficial transitional cell carcinoma of the bladder: a possible prognostic factor? Eur Urol 47: 52-57, 2005. PMID: 15582249. DOI: 10.1016/j.eururo.2004.08.004
    OpenUrlCrossRefPubMed
  92. ↵
    1. Zhang X,
    2. Li P,
    3. Bao J,
    4. Nicosia SV,
    5. Wang H,
    6. Enkemann SA,
    7. Bai W
    : Suppression of death receptor-mediated apoptosis by 1,25-dihydroxyvitamin D3 revealed by microarray analysis. J Biol Chem 280: 35458-35468, 2005. PMID: 16093247. DOI: 10.1074/jbc.M506648200
    OpenUrlAbstract/FREE Full Text
  93. ↵
    1. Lehmann B
    : Role of the vitamin D3 pathway in healthy and diseased skin – facts, contradictions and hypotheses. Exp Dermatol 18: 97-108, 2009. DOI: 10.1111/j.1600-0625.2008.00810.x
    OpenUrlCrossRefPubMed
  94. ↵
    1. Piotrowska A,
    2. Wierzbicka J,
    3. Żmijewski MA
    : Vitamin D in the skin physiology and pathology. Acta Biochim Pol 63: 17-29, 2016. PMID: 26824295. DOI: 10.18388/abp.2015_1104
    OpenUrlPubMed
  95. ↵
    1. Ramirez CC,
    2. Federman DG,
    3. Kirsner RS
    : Skin cancer as an occupational disease: the effect of ultraviolet and other forms of radiation. Int J Dermatol 44: 95-100, 2005. PMID: 15689204. DOI: 10.1111/j.1365-4632.2005.02301.x
    OpenUrlCrossRefPubMed
  96. ↵
    1. Brewer JD,
    2. Habermann TM,
    3. Shanafelt TD
    : Lymphoma-associated skin cancer: incidence, natural history, and clinical management. Int J Dermatol 53: 267-274, 2014. PMID: 24320558. DOI: 10.1111/ijd.12208
    OpenUrlPubMed
  97. ↵
    1. Giovannucci E
    : Vitamin D status and cancer incidence and mortality. Adv Exp Med Biol 624: 31-42, 2008. PMID: 18348445. DOI: 10.1007/978-0-387-77574-6_3
    OpenUrlCrossRefPubMed
    1. Tang JY,
    2. Fu T,
    3. Lau C,
    4. Oh DH,
    5. Bikle DD,
    6. Asgari MM
    : Vitamin D in cutaneous carcinogenesis: Part I. J Am Acad Dermatol 67: 803.e1-816, 2012. PMID: 23062903. DOI: 10.1016/j.jaad.2012.05.044
    OpenUrlPubMed
    1. Lerche CM,
    2. Philipsen PA,
    3. Poulsen T,
    4. Wulf HC
    : Topical hydrocortisone, clobetasol propionate, and calcipotriol do not increase photocarcinogenesis induced by simulated solar irradiation in hairless mice. Exp Dermatol 19: 973-979, 2010. PMID: 20113348. DOI: 10.1111/j.1600-0625.2009.01034.x
    OpenUrlPubMed
    1. Pommergaard HC,
    2. Burcharth J,
    3. Rosenberg J,
    4. Raskov H
    : Topical treatment with diclofenac, calcipotriol (vitamin-D3 analog) and difluoromethylornithine (DFMO) does not prevent nonmelanoma skin cancer in mice. Cancer Invest 31: 92-96, 2013. PMID: 23362949. DOI: 10.3109/07357907.2012.762782
    OpenUrlPubMed
    1. Reichrath J,
    2. Nürnberg B
    : Cutaneous vitamin D synthesis versus skin cancer development: The Janus faces of solar UV-radiation. Dermatoendocrinol 1: 253-261, 2009. PMID: 20808512.
    OpenUrlCrossRefPubMed
    1. Osborne JE,
    2. Hutchinson PE
    : Vitamin D and systemic cancer: is this relevant to malignant melanoma? Br J Dermatol 147: 197-213, 2002. PMID: 12174089.
    OpenUrlCrossRefPubMed
  98. ↵
    1. Chang Y,
    2. Barrett JH,
    3. Bishop DT,
    4. Armstrong BK,
    5. Bataille V,
    6. Bergman W,
    7. Berwick M,
    8. Bracci PM,
    9. Elwood JM,
    10. Ernstoff MS,
    11. Gallagher RP,
    12. Green AC,
    13. Gruis NA,
    14. Holly EA,
    15. Ingvar C,
    16. Kanetsky PA,
    17. Karagas MR,
    18. Lee TK,
    19. Le Marchand L,
    20. Mackie RM,
    21. Olsson H,
    22. Østerlind A,
    23. Rebbeck TR,
    24. Sasieni P,
    25. Siskind V,
    26. Swerdlow AJ,
    27. Titus-Ernstoff L,
    28. Zens MS,
    29. Newton-Bishop JA
    : Sun exposure and melanoma risk at different latitudes: a pooled analysis of 5700 cases and 7216 controls. Int J Epidemiol 38: 814-830, 2009. PMID: 19359257. DOI: 10.1093/ije/dyp166
    OpenUrlCrossRefPubMed
  99. ↵
    1. Dixon KM,
    2. Deo SS,
    3. Norman AW,
    4. Bishop JE,
    5. Halliday GM,
    6. Reeve VE,
    7. Mason RS
    : In vivo relevance for photoprotection by the vitamin D rapid response pathway. J Steroid Biochem Mol Biol 103: 451-456, 2007. PMID: 17223553. DOI: 10.1016/j.jsbmb.2006.11.016
    OpenUrlCrossRefPubMed
  100. ↵
    1. Mason RS,
    2. Reichrath J
    : Sunlight vitamin D and skin cancer. Anticancer Agents Med Chem 13: 83-97, 2013. PMID: 23094924.
    OpenUrlPubMed
  101. ↵
    1. Bataille V,
    2. Winnett A,
    3. Sasieni P,
    4. Newton Bishop JA,
    5. Cuzick J
    : Exposure to the sun and sunbeds and the risk of cutaneous melanoma in the UK: a case-control study. Eur J Cancer Oxf Engl 1990 40: 429-435, 2004. PMID: 14746862.
    OpenUrl
  102. ↵
    1. Asgari MM,
    2. Maruti SS,
    3. Kushi LH,
    4. White E
    : A cohort study of vitamin D intake and melanoma risk. J Invest Dermatol 129: 1675-1680, 2009. PMID: 19194478. DOI: 10.1038/jid.2008.451
    OpenUrlCrossRefPubMed
  103. ↵
    1. Reichrath J,
    2. Querings K
    : No evidence for reduced 25-hydroxyvitamin D serum level in melanoma patients. Cancer Causes Control CCC 15: 97-98, 2004. PMID: 15049326.
    OpenUrlPubMed
  104. ↵
    1. Kim JS,
    2. Jung M,
    3. Yoo J,
    4. Choi EH,
    5. Park BC,
    6. Kim MH,
    7. Hong SP
    : Protective effect of topical vitamin D3 against photocarcinogenesis in a murine model. Ann Dermatol 28: 304-313, 2016. PMID: 27274628. DOI: 10.5021/ad.2016.28.3.304
    OpenUrlPubMed
  105. ↵
    1. Dixon KM,
    2. Norman AW,
    3. Sequeira VB,
    4. Mohan R,
    5. Rybchyn MS,
    6. Reeve VE,
    7. Halliday GM,
    8. Mason RS
    : 1α,25(OH)2-vitamin D and a nongenomic vitamin D analogue inhibit ultraviolet radiation-induced skin carcinogenesis. Cancer Prev Res (Phila) 4: 1485-1494, 2011. PMID: 21733837. DOI: 10.1158/1940-6207.CAPR-11-0165
    OpenUrlAbstract/FREE Full Text
  106. ↵
    1. Makarova A,
    2. Wang G,
    3. Dolorito JA,
    4. Kc S,
    5. Libove E,
    6. Epstein EH
    : Vitamin D3 produced by skin exposure to UVR inhibits murine basal cell carcinoma carcinogenesis. J Invest Dermatol 137: 2613-2619, 2017. PMID: 28774592. DOI: 10.1016/j.jid.2017.05.037
    OpenUrlCrossRefPubMed
  107. ↵
    1. Bijlsma MF,
    2. Roelink H
    : Skin-derived vitamin D3 protects against basal cell carcinoma. J Invest Dermatol 137: 2469-2471, 2017. PMID: 29169462. DOI: 10.1016/j.jid.2017.07.816
    OpenUrlPubMed
  108. ↵
    1. Besaratinia A,
    2. Kim S-I,
    3. Pfeifer GP
    : Rapid repair of UVA-induced oxidized purines and persistence of UVB-induced dipyrimidine lesions determine the mutagenicity of sunlight in mouse cells. FASEB J 22: 2379-2392, 2008. PMID: 18326785. DOI: 10.1096/fj.07-105437
    OpenUrlCrossRefPubMed
    1. Mason RS,
    2. Sequeira VB,
    3. Dixon KM,
    4. Gordon-Thomson C,
    5. Pobre K,
    6. Dilley A,
    7. Mizwicki MT,
    8. Norman AW,
    9. Feldman D,
    10. Halliday GM,
    11. Reeve VE
    : Photoprotection by 1alpha,25-dihydroxyvitamin D and analogs: further studies on mechanisms and implications for UV-damage. J Steroid Biochem Mol Biol 121: 164-168, 2010. PMID: 20399269. DOI: 10.1016/j.jsbmb.2010.03.082
    OpenUrlCrossRefPubMed
  109. ↵
    1. Agar NS,
    2. Halliday GM,
    3. Barnetson RS,
    4. Ananthaswamy HN,
    5. Wheeler M,
    6. Jones AM
    : The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis. Proc Natl Acad Sci USA 101: 4954-4959, 2004. PMID: 15041750. DOI: 10.1073/pnas.0401141101
    OpenUrlAbstract/FREE Full Text
  110. ↵
    1. Gupta R,
    2. Dixon KM,
    3. Deo SS,
    4. Holliday CJ,
    5. Slater M,
    6. Halliday GM,
    7. Reeve VE,
    8. Mason RS
    : Photoprotection by 1,25 dihydroxyvitamin D3 is associated with an increase in p53 and a decrease in nitric oxide products. J Invest Dermatol 127: 707-715, 2007. PMID: 17170736. DOI: 10.1038/sj.jid.5700597
    OpenUrlCrossRefPubMed
  111. ↵
    1. Halliday GM
    : Inflammation, gene mutation and photoimmuno-suppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis. Mutat Res 571: 107-120, 2005. PMID: 15748642. DOI: 10.1016/j.mrfmmm.2004.09.013
    OpenUrlCrossRefPubMed
  112. ↵
    1. Wong G,
    2. Gupta R,
    3. Dixon KM,
    4. Deo SS,
    5. Choong SM,
    6. Halliday GM,
    7. Bishop JE,
    8. Ishizuka S,
    9. Norman AW,
    10. Posner GH,
    11. Mason RS
    : 1,25-Dihydroxyvitamin D and three low-calcemic analogs decrease UV-induced DNA damage via the rapid response pathway. J Steroid Biochem Mol Biol 89-90: 567-570, 2004. PMID: 15225840. DOI: 10.1016/j.jsbmb.2004.03.072
    OpenUrlPubMed
  113. ↵
    1. Dixon KM,
    2. Deo SS,
    3. Wong G,
    4. Slater M,
    5. Norman AW,
    6. Bishop JE,
    7. Posner GH,
    8. Ishizuka S,
    9. Halliday GM,
    10. Reeve VE,
    11. Mason RS
    : Skin cancer prevention: a possible role of 1,25dihydroxyvitamin D3 and its analogs. J Steroid Biochem Mol Biol 97: 137-143, 2005. PMID: 16039116. DOI: 10.1016/j.jsbmb.2005.06.006
    OpenUrlCrossRefPubMed
  114. ↵
    1. Grant WB
    : An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 94: 1867-1875, 2002. PMID: 11920550.
    OpenUrlCrossRefPubMed
  115. ↵
    1. Eide MJ,
    2. Weinstock MA
    : Association of UV index, latitude, and melanoma incidence in nonwhite populations--US Surveillance, Epidemiology, and End Results (SEER) Program, 1992 to 2001. Arch Dermatol 141: 477-481, 2005. PMID: 15837865. DOI: 10.1001/archderm.141.4.477
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Anticancer Research: 39 (7)
Anticancer Research
Vol. 39, Issue 7
July 2019
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
  • Back Matter (PDF)
  • Ed Board (PDF)
  • Front Matter (PDF)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word on Anticancer Research.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Potential Molecular Mechanisms of the Anti-cancer Activity of Vitamin D
(Your Name) has sent you a message from Anticancer Research
(Your Name) thought you would like to see the Anticancer Research web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
4 + 4 =
Solve this simple math problem and enter the result. E.g. for 1+3, enter 4.
Citation Tools
Potential Molecular Mechanisms of the Anti-cancer Activity of Vitamin D
DOROTA SKRAJNOWSKA, BARBARA BOBROWSKA-KORCZAK
Anticancer Research Jul 2019, 39 (7) 3353-3363; DOI: 10.21873/anticanres.13478

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Reprints and Permissions
Share
Potential Molecular Mechanisms of the Anti-cancer Activity of Vitamin D
DOROTA SKRAJNOWSKA, BARBARA BOBROWSKA-KORCZAK
Anticancer Research Jul 2019, 39 (7) 3353-3363; DOI: 10.21873/anticanres.13478
Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Vitamin D – Cell Cycle Regulation
    • Nuclear Vitamin D Receptor (nVDR)
    • Vitamin D – Apoptosis Induction
    • Vitamin D – Inhibition of Invasiveness and Metastasis of Tumours
    • Vitamin D – Angiogenesis Inhibition
    • Inhibition of Hedgehog (Hh) Signaling by Vitamin D
    • Interaction of p53 and VDR Signaling
    • Vitamin D – Interaction of Photocarcinogenesis
    • Conclusion
    • Acknowledgements
    • Footnotes
    • References
  • Info & Metrics
  • PDF

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • High Oral Vitamin D3 Intake Does Not Protect Against UVR-induced Squamous Cell Carcinoma in Mice
  • Cross-talk of Aryl Hydrocarbon Receptor (AHR)- and Vitamin D Receptor (VDR)-signaling in Human Keratinocytes
  • Newly-identified Pathways Relating Vitamin D to Carcinogenesis: A Review
  • Google Scholar

More in this TOC Section

  • Cytokine-based Cancer Immunotherapy: Challenges and Opportunities for IL-10
  • Proteolytic Enzyme Therapy in Complementary Oncology: A Systematic Review
  • Multimodal Treatment of Primary Advanced Ovarian Cancer
Show more Reviews

Similar Articles

Keywords

  • vitamin D
  • nVDR receptor
  • antitumor effect
  • review
Anticancer Research

© 2025 Anticancer Research

Powered by HighWire