Correlation between secosteroid-induced vitamin D receptor activity in melanoma cells and computer-modeled receptor binding strength
Open accessAbstract
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.
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20(OH)D3 and 20,23(OH)2D3 inhibit DNA synthesis and colony formation, cause cell cycle arrest, and stimulate keratinocyte differentiation with potency comparable to 1,25(OH)2D3.
“These secosteroids inhibit DNA synthesis and colony formation, cause cell cycle arrest and stimulate the differentiation program of keratinocytes with a potency comparable to that of 1,25(OH)2D3.”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [73]
17,20(OH)2D3 and 17,20,23(OH)3D3 have similar antiproliferative effects to 20(OH)D3 and 20,23(OH)2D3.
“Similar antiproliferative effects to those of 20(OH)D3 and 20,23(OH)2D3 are seen for 17,20(OH)2D3 and 17,20,23(OH)3D3”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [73]
1α-hydroxylated products 1,20(OH)2D3, 1,20(OH)2D2, and 1,20,23(OH)3D3 show similar inhibition of keratinocyte proliferation and stimulation of differentiation and VDR expression to their precursors, but greater stimulation of CYP24A1 expression.
“These products show similar inhibition of keratinocyte proliferation and stimulation of differentiation and VDR expression to those of their precursors, but display greater stimulation of CYP24A1 expression”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [73]
20(OH)D2 inhibits proliferation and induces the differentiation program of keratinocytes.
“Studies on vitamin D2-derived 20(OH)D2 have demonstrated that it can also inhibit proliferation and induce the differentiation program of keratinocytes”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [73]
These secosteroids do not act through the VDR A-pocket.
“suggesting that they do not act via the A-pocket [73].”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [73]
Molecular modeling with the VDR crystal structure predicts that 20S(OH)D3, 20S(OH)D2, and 20,23(OH)2D3 occupy the same binding pocket as 1,25(OH)2D3 and fit well.
“Molecular modeling using the VDR crystal structure has predicted that 20S(OH)D3/D2 and 20,23(OH)2D3 overlap well with the native ligand [1,25(OH)2D3], occupying the same binding pocket and showing an excellent fit [59,73,84,86].”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [73]
In modeled VDR complexes, these secosteroids orient their side chains toward the receptor surface and bury the secocholesta head deep in the pocket bottom.
“These secosteroids posed the side chains toward the surface of VDR and buried the secocholesta head deeply inside the pocket bottom [73].”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [73]
The phenotypic effects of these secosteroids correlate with ligand-induced translocation of the vitamin D receptor to the nucleus.
“Also, the phenotypic effects correlate well with ligand-induced translocation of the VDR to the nucleus [48,59,73,78].”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [73]
Docking scores for binding to the VDR non-genomic A-pocket were poor.
“In contrast, docking scores for binding to the non-genomic binding site [A-pocket] of the VDR were poor”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [73]
There is sufficient experimental data to justify further preclinical testing of these novel secosteroids in melanoma.
“In the case of melanoma, there is already sufficient experimental data to justify further preclinical testing of these novel secosteroids [53,56,59,63–65,71,73,77,78,80,81,91,92].”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [73]
Novel secosteroids act as biased agonists at the vitamin D receptor, with selectivity for certain receptor-mediated effects, and can also interact with RORα and RORγ, presumably as inverse agonists.
“Importantly, the novel secosteroids in addition to acting as biased agonists on the vitamin D receptor (showing selectivity for certain receptor mediated effects) [103,112,122], can also interact with RORα and γ, presumably acting as inverse agonists [123].”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [122]
These secosteroids have cell-type-dependent phenotypic effects secondary to binding VDR and/or RORα and γ as reverse agonists.
“They also express diverse phenotypic effects dependent on cell type (reviewed in [52, 65, 66]) that are secondary to binding to either the VDR, and/or to RORα and γ on which they act as reverse agonists [20, 21, 67, 178–183].”
From The serum vitamin D metabolome: what we know and what is still to discover (2019) · cites this paper as [183]
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- Authors
- Kim, T.-K., Wang, J., Janjetovic, Z., Chen, J., Tuckey, R. C., Nguyen, M. N., Tang, E. K. Y., Miller, D., Li, W., & Slominski, A. T.
- Affiliations
- University of Tennessee Health Science Center (US)
- The University of Western Australia (AU)
- Corresponding author
- Slominski, Andrzej T.
- ORCID
- Venue
- Molecular and Cellular Endocrinology
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 361
- Issue
- 1-2
- Pages
- 143-152
- ISSN
- 0303-7207 (ISSN-L)
- PMC
- PMC3409337
- OpenAlex
- W2108296645
- Cited by
- 67
- References
- 32
- Citations by year
- 2024: 3 · 2023: 2 · 2022: 7 · 2021: 5 · 2020: 8 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 6 · 2015: 8 · 2014: 6 · 2013: 4 · 2012: 2
- FWCI
- 4.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Funders
- Western University of Health Sciences
- National Institutes of Health
- Health Science Center, University of Tennessee
- National Cancer Institute (R01CA148706)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR052190, R01AR056666)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Vitamin D Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- secosteroids, vitamin D receptor, melanoma cells, cytochrome P450scc, ligand binding affinity, molecular docking, side chain length, hydroxyl group position, receptor activation, cell proliferation inhibition
- MeSH terms
- Epidermal Cells, Cell Nucleus, Cholecalciferol, Cholesterol Side-Chain Cleavage Enzyme, Computer Simulation, Humans, Melanoma, Models, Molecular, Protein Binding, Secosteroids, Keratinocytes, Receptors, Calcitriol, Protein Transport, Cell Proliferation, Molecular Docking Simulation
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