title: A Functional and Putative Physiological Role of Calcitriol in Patched1/Smoothened Interaction.
abstract: The Patched1 (Ptch)-mediated inhibition of Smoothened (Smo) is still an open question. However, a direct Ptch/Smo interaction has been excluded, Smo modulators were identified, but the endogenous signal transmitting molecule remains undiscovered. Here, we demonstrate that calcitriol, the hormonally active form of vitamin D3, is an excellent candidate for transmission of Ptch/Smo interaction. Our study reveals that Ptch expression is sufficient to release calcitriol from the cell and that calcitriol inhibits Smo action and ciliary translocation by acting on a site distinct from the 7-transmembrane domain or the cysteine-rich domain. Moreover calcitriol strongly synergizes with itraconazole (ITZ) in Smo inhibition, which did not result from elevated calcitriol bioavailability due to ITZ-mediated 24-hydroxylase inhibition but rather from a direct interaction of the compounds at the level of Smo. Together, we suggest that calcitriol represents a possible endogenous transmitter of Ptch/Smo interaction. Moreover calcitriol or calcitriol derivatives combined with ITZ might be a treatment option of Hedgehog-associated cancers.
authors.affiliation: From the Institute of Human Genetics, Tumor Genetics Group, and.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Linder
authors.affiliation: the Department Genome Analysis Centre, Institute for Experimental Genetics, Helmholtz Zentrum Muenchen, National Research Center for Environment and Health, 85764 Neuherberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Weber
authors.affiliation: the Institute of Cellular and Molecular Immunology, University Medical Center, 37073 Goettingen and.
authors.forename: Kai
authors.initials: K
authors.lastname: Dittmann
authors.affiliation: the Department Genome Analysis Centre, Institute for Experimental Genetics, Helmholtz Zentrum Muenchen, National Research Center for Environment and Health, 85764 Neuherberg, Germany.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: From the Institute of Human Genetics, Tumor Genetics Group, and.
authors.forename: Heidi
authors.initials: H
authors.lastname: Hahn
authors.affiliation: From the Institute of Human Genetics, Tumor Genetics Group, and auhmann@gwdg.de.
authors.forename: Anja
authors.initials: A
authors.lastname: Uhmann
mesh_terms: D000818:Animals; D001665:Binding Sites; D002117:Calcitriol / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor
chemical_list: C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D017964:Itraconazole; D008156:Luciferases; D002117:Calcitriol
keywords: Hedgehog signaling pathway; cancer; cancer therapy; cell signaling; signal transduction; vitamin D