title: Glucocorticoid compounds modify smoothened localization and hedgehog pathway activity.
abstract: The Hedgehog signaling pathway is linked to a variety of diseases, notably a range of cancers. The first generation of drug screens identified Smoothened (Smo), a membrane protein essential for signaling, as an attractive drug target. Smo localizes to the primary cilium upon pathway activation, and this transition is critical for the response to Hedgehog ligands. In a high content screen directly monitoring Smo distribution in Hedgehog-responsive cells, we identified different glucocorticoids as specific modulators of Smo ciliary accumulation. One class promoted Smo accumulation, conferring cellular hypersensitivity to Hedgehog stimulation. In contrast, a second class inhibited Smo ciliary localization and signaling activity by both wild-type Smo, and mutant forms of Smo, SmoM2, and SmoD473H, that are refractory to previously identified Smo antagonists. These findings point to the potential for developing glucocorticoid-based pharmacological modulation of Smo signaling to treat mutated drug-resistant forms of Smo, an emerging problem in long-term cancer therapy. They also raise a concern about potential crosstalk of glucocorticoid drugs in the Hedgehog pathway, if therapeutic administration exceeds levels associated with on-target transcriptional mechanisms of glucocorticoid action.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Lance
authors.initials: L
authors.lastname: Davidow
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Arvanites
authors.forename: Joel
authors.initials: J
authors.lastname: Blanchard
authors.forename: Kelvin
authors.initials: K
authors.lastname: Lam
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.forename: Vatsal
authors.initials: V
authors.lastname: Oza
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Yoo
authors.forename: Jessica M Y
authors.initials: JM
authors.lastname: Ng
authors.forename: Tom
authors.initials: T
authors.lastname: Curran
authors.forename: Lee L
authors.initials: LL
authors.lastname: Rubin
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004347:Drug Interactions; D005446:Fluocinolone Acetonide / Q000494:pharmacology; D005938:Glucocorticoids / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D000072079:Patched Receptors; D011725:Pyridines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor
chemical_list: D000813:Anilides; D005938:Glucocorticoids; D053823:Hedgehog Proteins; C538724:HhAntag691; D000072079:Patched Receptors; D011725:Pyridines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D005446:Fluocinolone Acetonide