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

  • Sci Rep. 2017 Sep 12;7(1):11434. doi: 10.1038/s41598-017-10202-7.
Andrzej T Slominski  1  2  3  4 ,  Tae-Kang Kim  5 ,  Judith V Hobrath  6 ,  Zorica Janjetovic  5 ,  Allen S W Oak  5 ,  Arnold Postlethwaite  7 ,  Zongtao Lin  8 ,  Wei Li  8 ,  Yukimasa Takeda  9 ,  Anton M Jetten  9 ,  Robert C Tuckey  10
Affiliations
  • 1. Department of Dermatology, VA Medical Center, Birmingham, AL, 35249, USA. [email protected].
  • 2. Comprehensive Cancer Center, Cancer Chemoprevention Program, VA Medical Center, Birmingham, AL, 35249, USA. [email protected].
  • 3. Nutrition Obesity Research Center, University of Alabama at Birmingham, VA Medical Center, Birmingham, AL, 35249, USA. [email protected].
  • 4. Pathology and Laboratory Medicine Service, VA Medical Center, Birmingham, AL, 35249, USA. [email protected].
  • 5. Department of Dermatology, VA Medical Center, Birmingham, AL, 35249, USA.
  • 6. Drug Discovery Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
  • 7. Department of Medicine, Division of Rheumatology and Connective Tissue Diseases, University of Tennessee HSC, and Memphis VA Medical Center, Memphis, TN, 38163, USA.
  • 8. Department of Pharmaceutical Sciences, University of Tennessee HSC, Memphis, TN, 38163, USA.
  • 9. Cell Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, 27709, USA.
  • 10. School of Molecular Sciences, The University of Western Australia, Perth, WA, Australia.
PMID: 28900196 DOI: 10.1038/s41598-017-10202-7
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.

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