Probing seco-steroid inhibition of the hedgehog signaling pathway
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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.
KeywordsVitamin D3 Calcitriol Hedgehog signaling Mouse embryonic fibroblast TGF-β
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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Conflict of interest
The authors declare no conflict of interest in regard to the information presented in this manuscript.
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