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Probing seco-steroid inhibition of the hedgehog signaling pathway

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Abstract

Calcitriol, vitamin D3 (VD3), and structurally related VD3 analogues are inhibitors of Hh signaling in multiple contexts and are promising anti-cancer agents in Hh-dependent forms of cancer; however, the cellular mechanisms through which these compounds regulate Hh signal transmission are not clearly defined. Previous studies in this area have implicated both Smoothened, a key mediator of Hh signaling, and the vitamin D receptor (VDR) as potential mediators of Hh inhibition for this class of seco-steroids. We have performed a series of in vitro studies to more fully probe the cellular mechanisms that govern seco-steroid-mediated inhibition of Hh signaling. Our results support a role for both the Hh and VDR pathways in this process, as well as the possibility that other, as yet unidentified proteins, are also central to seco-steroid-mediated inhibition of Hh signaling.

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Acknowledgements

The authors gratefully acknowledge support of this work by the American Cancer Society (RSG-13-131-01), the National Science Foundation (1515808), and the University of Connecticut Research Foundation. The Ptch−/− and Sufu−/− MEFs were a kind gift from Matthew Scott (Stanford University). The VDR−/− MEFs were a kind gift from Jun Sun (University of Illinois College of Medicine). Smo−/− MEFs were a kind gift from Philip Beachy (Stanford University).

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  1. Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Unit 3092, Storrs, CT, 06269-3092, USA

    Evrett N. Thompson, Vibhavari Sail, Daniel S. Raccuia & M. Kyle Hadden

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  1. Evrett N. Thompson
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  2. Vibhavari Sail
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  3. Daniel S. Raccuia
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Correspondence to M. Kyle Hadden.

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Thompson, E.N., Sail, V., Raccuia, D.S. et al. Probing seco-steroid inhibition of the hedgehog signaling pathway. Mol Cell Biochem 450, 75–85 (2019). https://doi.org/10.1007/s11010-018-3374-0

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  • DOI: https://doi.org/10.1007/s11010-018-3374-0

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