Glucocorticoid Compounds Modify Smoothened Localization and Hedgehog Pathway Activity

Details

• Alternative Title:
  Chem Biol
• Personal Author:
  Wang, Yu ; Davidow, Lance ; Arvanites, Anthony C. ; Blanchard, Joel ; Lam, Kelvin ; Xu, Ke ; Oza, Vatsal ; Yoo, Jin Woo ; Ng, Jessica M.Y. ; Curran, Tom ; Rubin, Lee L. ; McMahon, Andrew P.
• Description:
  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.
• Subjects:
  Anilides Animals Cell Proliferation Cells, Cultured Chlorocebus Aethiops COS Cells Drug Interactions Fluocinolone Acetonide Glucocorticoids Hedgehog Proteins HEK293 Cells Humans Mice NIH 3T3 Cells Patched Receptors Pyridines Receptors, Cell Surface Receptors, G-Protein-Coupled Signal Transduction Smoothened Receptor

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• Source:
  Chem Biol. 2012; 19(8):972-982
• Pubmed ID:
  22921064
• Pubmed Central ID:
  PMC3724998
• Document Type:
  Journal Article
• Funding:
  P01 CA096832/CA/NCI NIH HHSUnited States/ ; R01 NS033642/NS/NINDS NIH HHSUnited States/ ; R37 NS033642/NS/NINDS NIH HHSUnited States/ ; U48 DP000033/DP/NCCDPHP CDC HHSUnited States/
• Volume:
  19
• Issue:
  8
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:3d6115f014273b410e986654c2bdc5c3133a8a486d1e8ee93c4d247cf7aa7934
• Download URL:
  https://stacks.cdc.gov/view/cdc/41900/cdc_41900_DS1.pdf
• File Type:
  [PDF - 1.92 MB ]