Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

Slominski, Andrzej; Kim, Tae Kang; Hobrath, Judith V.; Oak, Allen S.W.; Tang, Edith K.Y.; Tieu, Elaine W.; Li, Wei; Tuckey, Robert C.; Jetten, Anton M.

doi:10.1016/j.jsbmb.2016.09.024

Cited by 126 publications

(162 citation statements)

References 105 publications

(170 reference statements)

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“…VDR expression was identified in many tissues and cells, including epidermal and dermal skin cells that both synthesize 1,25(OH) 2 D 3 (calcitriol) and respond to it (10,107,(113)(114)(115). Noncanonical, noncalcemic hydroxylated vitamin D 3 forms (9, 30, 33) can also act on VDR (116)(117)(118)(119). They can also act as inverse agonists on retinoic acid-related orphan receptors (RORs) α and γ (117,120), which are expressed in normal and pathological skin cells, including melanoma (120,121).…”

Section: Classical and Non-classical Vitamin D Derivativesmentioning

confidence: 99%

Relevance of Vitamin D in Melanoma Development, Progression and Therapy

2019

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Melanoma is one of the most lethal types of skin cancer, with a poor prognosis once the disease enters metastasis. The efficacy of currently available treatment schemes for advanced melanomas is low, expensive, and burdened by significant side-effects. Therefore, there is a need to develop new treatment options. Skin cells are able to activate vitamin D via classical and non-classical pathways. Vitamin D derivatives have anticancer properties which promote differentiation and inhibit proliferation. The role of systemic vitamin D in patients with melanoma is unclear as epidemiological studies are not definitive. In contrast, experimental data have clearly shown that vitamin D and its derivatives have anti-melanoma properties. Furthermore, molecular and clinicopathological studies have demonstrated a correlation between defects in vitamin D signaling and progression of melanoma and disease outcome. Therefore, adequate vitamin D signaling can play a role in the treatment of melanoma. Skin cells are able to activate vitamin D via classical and nonclassical metabolic pathways (1-9). Vitamin D derivatives have anticancer properties and promote differentiation and inhibit proliferation of various cells, including melanoma, the most aggressive and lethal type of skin cancer. In this review, we provide an overview on the endogenous synthesis and activation of vitamin D via classical and non-classical pathways. We also present the association of vitamin D and melanoma based on epidemiological, experimental and clinical evidence, showing that defects in vitamin D signaling correlate with progression of melanoma and disease outcome. Therefore, restoration of the adequate vitamin D signaling can play a role in melanoma therapy. 473 This article is freely accessible online.

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Section: Classical and Non-classical Vitamin D Derivativesmentioning

confidence: 99%

Relevance of Vitamin D in Melanoma Development, Progression and Therapy

2019

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“…94–96 Thus, in addition to the well-established mechanism of activation by binding of active forms of vitamin D to the genomic site of the VDR, there are non-genomic membrane-associated sites of action (A-VDR and 1,25D3-MARRS) as well as other nuclear receptor targets comprising ROR- α and -γ . 95 The regulatory targets for pD and aD secosteroids or lumisterol compounds remain to be identified.…”

Section: Vitamin D In a ‘Nutshell’mentioning

confidence: 99%

Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

Slominski

Brożyna

Żmijewski

et al. 2017

Laboratory Investigation

118

128

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Ultraviolet B (UVB), in addition to having carcinogenic activity, is required for the production of vitamin D3 (D3) in the skin which supplies >90% of the body's requirement. Vitamin D is activated through hydroxylation by 25-hydroxylases (CYP2R1 or CYP27A1) and 1α-hydroxylase (CYP27B1) to produce 1,25(OH)2D3, or through the action of CYP11A1 to produce mono-di- and trihydroxy-D3 products that can be further modified by CYP27B1, CYP27A1, and CYP24A1. The active forms of D3, in addition to regulating calcium metabolism, exert pleiotropic activities, which include anticarcinogenic and anti-melanoma effects in experimental models, with photoprotection against UVB-induced damage. These diverse effects are mediated through an interaction with the vitamin D receptor (VDR) and/or as most recently demonstrated through action on retinoic acid orphan receptors (ROR)α and RORγ. With respect to melanoma, low levels of 25(OH)D are associated with thicker tumors and reduced patient survival. Furthermore, single-nucleotide polymorphisms of VDR and the vitamin D-binding protein (VDP) genes affect melanomagenesis or disease outcome. Clinicopathological analyses have shown positive correlation between low or undetectable expression of VDR and/or CYP27B1 in melanoma with tumor progression and shorter overall (OS) and disease-free survival (DFS) times. Paradoxically, this correlation was reversed for CYP24A1 (inactivating 24-hydroxylase), indicating that this enzyme, while inactivating 1,25(OH)2D3, can activate other forms of D3 that are products of the non-canonical pathway initiated by CYP11A1. An inverse correlation has been found between the levels of RORα and RORγ expression and melanoma progression and disease outcome. Therefore, we propose that defects in vitamin D signaling including D3 activation/inactivation, and the expression and activity of the corresponding receptors, affect melanoma progression and the outcome of the disease. The existence of multiple bioactive forms of D3 and alternative receptors affecting the behavior of melanoma should be taken into consideration when applying vitamin D management for melanoma therapy.

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“…NRs, highly conserved transcription factors, regulate a variety of biological processes under normal and pathological conditions, including cell differentiation, immune response, circadian rhythm, lipid, steroid, xenobiotic and glucose metabolism, (reviewed in). Vitamin D receptor (VDR) are targets for bioregulatory functions of 1,25(OH) 2 D3 and novel CYP11A1 derived vitamin D‐hydroxyderivatives in skin cancers. In addition, vitamin D and lumisterol hydroxyderivatives can act on RORα, RORγ as inverse agonists and CYP11A1‐derived vitamin D metabolites also act as agonists on aryl hydrocarbon receptor (AhR) .…”

Section: Introductionmentioning

confidence: 99%

“…Vitamin D receptor (VDR) are targets for bioregulatory functions of 1,25(OH) 2 D3 and novel CYP11A1 derived vitamin D‐hydroxyderivatives in skin cancers. In addition, vitamin D and lumisterol hydroxyderivatives can act on RORα, RORγ as inverse agonists and CYP11A1‐derived vitamin D metabolites also act as agonists on aryl hydrocarbon receptor (AhR) . Recently, several studies showed that the expression of VDR could be regulated by hypoxia .…”

Section: Introductionmentioning

confidence: 99%

On the relationship between VDR, RORα and RORγ receptors expression and HIF1‐α levels in human melanomas

Brożyna

Jóźwicki

Jetten

et al. 2019

Experimental Dermatology

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We analysed the correlation between the expression of HIF‐1α (hypoxia‐inducible factor 1 alpha), the nuclear receptors: VDR (vitamin D receptor), RORα (retinoic acid receptor‐related orphan receptor alpha), and RORγ and CYP24A1 (cytochrome P450 family 24 subfamily A member 1) and CYP27B1 (cytochrome P450 family 27 subfamily B member 1), enzymes involved in vitamin D metabolism. In primary and metastatic melanomas, VDR negatively correlated with nuclear HIF‐1α expression (r = −.2273, P = .0302; r = −.5081, P = .0011). Furthermore, the highest HIF‐1α expression was observed in pT3‐pT4 VDR‐negative melanomas. A comparative analysis of immunostained HIF‐1α and CYP27B1 and CYP24A1 showed lack of correlation between these parameters both in primary tumors and melanoma metastases. In contrast, RORα expression correlated positively with nuclear HIF‐1α expression in primary and metastatic lesions (r = .2438, P = .0175; r = .3662, P = .0166). Comparable levels of HIF‐1α expression pattern was observed in localized and advanced melanomas. RORγ in primary melanomas correlated also positively with nuclear HIF‐1α expression (r = .2743, P = .0129). HIF‐1α expression was the lowest in localized RORγ‐negative melanomas. In addition, HIF‐1α expression correlated with RORγ‐positive lymphocytes in melanoma metastases. We further found that in metastatic lymph nodes FoxP3 immunostaining correlated positively with HIF‐1α and RORγ expression in melanoma cells (r = .3667; P = .0327; r = .4208, P = .0129). In summary, our study indicates that the expression of VDR, RORα and RORγ in melanomas is related to hypoxia and/or HIF1‐α activity, which also affects FoxP3 expression in metastatic melanoma. Therefore, the hypoxia can affect tumor biology by changing nuclear receptors expression and molecular pathways regulated by nuclear receptors and immune responses.

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Endogenously produced nonclassical vitamin D hydroxy-metabolites act as “biased” agonists on VDR and inverse agonists on RORα and RORγ

Cited by 126 publications

References 105 publications

Relevance of Vitamin D in Melanoma Development, Progression and Therapy

Relevance of Vitamin D in Melanoma Development, Progression and Therapy

Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management

On the relationship between VDR, RORα and RORγ receptors expression and HIF1‐α levels in human melanomas

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