Glucocorticoid Compounds Modify Smoothened Localization and Hedgehog Pathway Activity

SummaryThe 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (139 K)Download as PowerPoint slideHighlights► Screened compound libraries for modulation of Smo movement to the primary cilium ► Identified glucocorticoids inducing Smo ciliary accumulation without activation ► They sensitize cells to Hh input and potentially modify the efficacy of Smo antagonists ► Identified a glucocorticoid inhibitor effective in inhibiting drug-resistant Smo mutants