Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-09-12

AUTHORS

Andrzej T. Slominski, Tae-Kang Kim, Judith V. Hobrath, Zorica Janjetovic, Allen S. W. Oak, Arnold Postlethwaite, Zongtao Lin, Wei Li, Yukimasa Takeda, Anton M. Jetten, Robert C. Tuckey

ABSTRACT

Using LC/qTOF-MS we detected lumisterol, 20-hydroxylumisterol, 22-hydroxylumisterol, 24-hydroxylumisterol, 20,22-dihydroxylumisterol, pregnalumisterol, 17-hydroxypregnalumisterol and 17,20-dihydroxypregnalumisterol in human serum and epidermis, and the porcine adrenal gland. The hydroxylumisterols inhibited proliferation of human skin cells in a cell type-dependent fashion with predominant effects on epidermal keratinocytes. They also inhibited melanoma proliferation in both monolayer and soft agar. 20-Hydroxylumisterol stimulated the expression of several genes, including those associated with keratinocyte differentiation and antioxidative responses, while inhibiting the expression of others including RORA and RORC. Molecular modeling and studies on VDRE-transcriptional activity excludes action through the genomic site of the VDR. However, their favorable interactions with the A-pocket in conjunction with VDR translocation studies suggest they may act on this non-genomic VDR site. Inhibition of RORα and RORγ transactivation activities in a Tet-on CHO cell reporter system, RORα co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified RORα and RORγ as excellent receptor candidates for the hydroxylumisterols. Thus, we have discovered a new biologically relevant, lumisterogenic pathway, the metabolites of which display biological activity. This opens a new area of endocrine research on the effects of the hydroxylumisterols on different pathways in different cells and the mechanisms involved. More... »

PAGES

11434

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-017-10202-7

DOI

http://dx.doi.org/10.1038/s41598-017-10202-7

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28900196


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28 schema:description Using LC/qTOF-MS we detected lumisterol, 20-hydroxylumisterol, 22-hydroxylumisterol, 24-hydroxylumisterol, 20,22-dihydroxylumisterol, pregnalumisterol, 17-hydroxypregnalumisterol and 17,20-dihydroxypregnalumisterol in human serum and epidermis, and the porcine adrenal gland. The hydroxylumisterols inhibited proliferation of human skin cells in a cell type-dependent fashion with predominant effects on epidermal keratinocytes. They also inhibited melanoma proliferation in both monolayer and soft agar. 20-Hydroxylumisterol stimulated the expression of several genes, including those associated with keratinocyte differentiation and antioxidative responses, while inhibiting the expression of others including RORA and RORC. Molecular modeling and studies on VDRE-transcriptional activity excludes action through the genomic site of the VDR. However, their favorable interactions with the A-pocket in conjunction with VDR translocation studies suggest they may act on this non-genomic VDR site. Inhibition of RORα and RORγ transactivation activities in a Tet-on CHO cell reporter system, RORα co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified RORα and RORγ as excellent receptor candidates for the hydroxylumisterols. Thus, we have discovered a new biologically relevant, lumisterogenic pathway, the metabolites of which display biological activity. This opens a new area of endocrine research on the effects of the hydroxylumisterols on different pathways in different cells and the mechanisms involved.
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35 Biologically
36 LC/QTOF-MS
37 Luc reporter activity
38 QTOF-MS
39 RORA
40 RORC
41 RORα
42 RORγ
43 Tet
44 VDR
45 action
46 activity
47 adrenal gland
48 agar
49 antioxidative response
50 area
51 assays
52 biological activity
53 candidates
54 cell reporter system
55 cell type-dependent fashion
56 cells
57 characterization
58 conjunction
59 different cells
60 different pathways
61 differentiation
62 effect
63 endocrine research
64 epidermal keratinocytes
65 epidermis
66 expression
67 fashion
68 favorable interactions
69 genes
70 genomic sites
71 gland
72 human serum
73 human skin cells
74 inhibition
75 interaction
76 keratinocyte differentiation
77 keratinocytes
78 lumisterol
79 mechanism
80 melanoma proliferation
81 metabolites
82 modeling
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84 monolayers
85 new areas
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89 porcine adrenal glands
90 predominant effect
91 proliferation
92 receptor candidates
93 reporter activity
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