title: Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis.
abstract: UAB30 is an RXR selective agonist that has been shown to have potential cancer chemopreventive properties. Due to high efficacy and low toxicity, it is currently being evaluated in human Phase I clinical trials by the National Cancer Institute. While UAB30 shows promise as a low toxicity chemopreventive drug, the mechanism of its action is not well understood. In this study, we investigated the effects of UAB30 on gene expression in human organotypic skin raft cultures and mouse epidermis. The results of this study indicate that treatment with UAB30 results in upregulation of genes responsible for the uptake and metabolism of all-trans-retinol to all-trans-retinoic acid (ATRA), the natural agonist of RAR nuclear receptors. Consistent with the increased expression of these genes, the steady-state levels of ATRA are elevated in human skin rafts. In ultraviolet B (UVB) irradiated mouse skin, the expression of ATRA target genes is found to be reduced. A reduced expression of ATRA sensitive genes is also observed in epidermis of mouse models of UVB-induced squamous cell carcinoma and basal cell carcinomas. However, treatment of mouse skin with UAB30 prior to UVB irradiation prevents the UVB-induced decrease in expression of some of the ATRA-responsive genes. Considering its positive effects on ATRA signaling in the epidermis and its low toxicity, UAB30 could be used as a chemoprophylactic agent in the treatment of non-melanoma skin cancer, particularly in organ transplant recipients and other high risk populations.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35294, United States of America.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35294, United States of America.
authors.forename: Sandeep C
authors.initials: SC
authors.lastname: Chaudhary
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, 35294, United States of America.
authors.forename: Venkatram R
authors.initials: VR
authors.lastname: Atigadda
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35294, United States of America.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Belyaeva
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, 35294, United States of America.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Harville
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35294, United States of America.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Elmets
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, 35294, United States of America.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Muccio
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35294, United States of America.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35294, United States of America.
authors.forename: Natalia Y
authors.initials: NY
authors.lastname: Kedishvili
mesh_terms: D000818:Animals; D053898:Biosynthetic Pathways / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism; D014212:Tretinoin / Q000032:analysis / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D005231:Fatty Acids, Unsaturated; D009281:Naphthalenes; D047488:Retinoid X Receptors; D014212:Tretinoin; C112106:UAB 30