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Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis

Victoria M. Wu, Steven C. Chen, Michelle R. Arkin and Jeremy F. Reiter
Proceedings of the National Academy of Sciences of the United States of America
Vol. 109, No. 34 (August 21, 2012), pp. 13644-13649
Stable URL: http://www.jstor.org/stable/41700985
Page Count: 6
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Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis
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Abstract

Vertebrate Hedgehog (Hh) signals involved in development and some forms of cancer, such as basal cell carcinoma, are transduced by the primary cilium, a microtubular projection found on many cells. A critical step in vertebrate Hh signal transduction is the regulated movement of Smoothened (Smo), a seven-transmembrane protein, to the primary cilium. To identify small molecules that interfere with either the ciliary localization of Smo or ciliogenesis, we undertook a high-throughput microscopy-based screen for compounds that alter the ciliary localization of YFP-tagged Smo. This screen identified 10 compounds that inhibit Hh pathway activity. Nine of these Smo antagonists (SA1-9) bind Smo, and one (SA10) does not. We also identified two compounds that inhibit ciliary biogenesis, which block microtubule polymerization or alter centrosome composition. Differential labeling of cell surface and intracellular Smo pools indicates that SA1-7 and 10 specifically inhibit trafficking of intracellular Smo to cilia. In contrast SA8 and 9 recruit endogenous Smo to the cilium in some cell types. Despite these different mechanisms of action, all of the SAs inhibit activation of the Hh pathway by an oncogenic form of Smo, and abrogate the proliferation of basal cell carcinoma-like cancer cells. The SA compounds may provide alternative means of inhibiting pathogenic Hh signaling, and our study reveals that different pools of Smo move into cilia through distinct mechanisms.

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