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J Biol Chem. 2015 Aug 7;290(32):19614-28. doi: 10.1074/jbc.M115.646141. Epub 2015 Jun 30.

A Functional and Putative Physiological Role of Calcitriol in Patched1/Smoothened Interaction.

Author information

1
From the Institute of Human Genetics, Tumor Genetics Group, and.
2
the Department Genome Analysis Centre, Institute for Experimental Genetics, Helmholtz Zentrum Muenchen, National Research Center for Environment and Health, 85764 Neuherberg, Germany.
3
the Institute of Cellular and Molecular Immunology, University Medical Center, 37073 Goettingen and.
4
From the Institute of Human Genetics, Tumor Genetics Group, and auhmann@gwdg.de.

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.

KEYWORDS:

Hedgehog signaling pathway; cancer; cancer therapy; cell signaling; signal transduction; vitamin D

PMID:
26126827
PMCID:
PMC4528127
DOI:
10.1074/jbc.M115.646141
[Indexed for MEDLINE]
Free PMC Article

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