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

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

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 ROR alpha and ROR gamma transactivation activities in a Tet-on CHO cell reporter system, ROR alpha co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified ROR alpha and ROR gamma 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.

Original languageEnglish
Article number11434
Number of pages17
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 12 Sep 2017

Cite this

Slominski, Andrzej T. ; Kim, Tae-Kang ; Hobrath, Judith V. ; Janjetovic, Zorica ; Oak, Allen S. W. ; Postlethwaite, Arnold ; Lin, Zongtao ; Li, Wei ; Takeda, Yukimasa ; Jetten, Anton M. ; Tuckey, Robert C. / Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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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 ROR alpha and ROR gamma transactivation activities in a Tet-on CHO cell reporter system, ROR alpha co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified ROR alpha and ROR gamma 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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author = "Slominski, {Andrzej T.} and Tae-Kang Kim and Hobrath, {Judith V.} and Zorica Janjetovic and Oak, {Allen S. W.} and Arnold Postlethwaite and Zongtao Lin and Wei Li and Yukimasa Takeda and Jetten, {Anton M.} and Tuckey, {Robert C.}",
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Slominski, AT, Kim, T-K, Hobrath, JV, Janjetovic, Z, Oak, ASW, Postlethwaite, A, Lin, Z, Li, W, Takeda, Y, Jetten, AM & Tuckey, RC 2017, 'Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols' Scientific Reports, vol. 7, no. 1, 11434. https://doi.org/10.1038/s41598-017-10202-7

Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols. / Slominski, Andrzej T.; Kim, Tae-Kang; Hobrath, Judith V.; Janjetovic, Zorica; Oak, Allen S. W.; Postlethwaite, Arnold; Lin, Zongtao; Li, Wei; Takeda, Yukimasa; Jetten, Anton M.; Tuckey, Robert C.

In: Scientific Reports, Vol. 7, No. 1, 11434, 12.09.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols

AU - Slominski, Andrzej T.

AU - Kim, Tae-Kang

AU - Hobrath, Judith V.

AU - Janjetovic, Zorica

AU - Oak, Allen S. W.

AU - Postlethwaite, Arnold

AU - Lin, Zongtao

AU - Li, Wei

AU - Takeda, Yukimasa

AU - Jetten, Anton M.

AU - Tuckey, Robert C.

PY - 2017/9/12

Y1 - 2017/9/12

N2 - 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 ROR alpha and ROR gamma transactivation activities in a Tet-on CHO cell reporter system, ROR alpha co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified ROR alpha and ROR gamma 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.

AB - 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 ROR alpha and ROR gamma transactivation activities in a Tet-on CHO cell reporter system, ROR alpha co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified ROR alpha and ROR gamma 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.

KW - CYTOCHROME P450SCC CYP11A1

KW - PITUITARY-ADRENAL AXIS

KW - BASAL-CELL CARCINOMA

KW - VITAMIN-D METABOLISM

KW - KAPPA-B ACTIVITY

KW - EPIDERMAL-KERATINOCYTES

KW - ULTRAVIOLET-RADIATION

KW - MELANIN PIGMENTATION

KW - MAMMALIAN SKIN

KW - D ANALOGS

U2 - 10.1038/s41598-017-10202-7

DO - 10.1038/s41598-017-10202-7

M3 - Article

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 11434

ER -