Editors' ChoiceCell Biology

Endocannabinoids inhibit Hedgehog signaling

Sci. Signal.  31 Mar 2015:
Vol. 8, Issue 370, pp. ec75
DOI: 10.1126/scisignal.aab2079

The Hedgehog (Hh) pathway regulates embryonic development and adult tissue homeostasis. Increased activation of the transmembrane protein Smoothened (SMO) contributes to cancer and other diseases. Endocannabinoids are lipids that activate cannabinoid receptors in the brain and peripheral nervous system to modify various processes—including appetite, pain sensation, mood, and memory—and they can suppress the growth of tumors with increased Hh activity. By isolating lipids in Drosophila wing imaginal discs using chromatography-based fractionation and mass spectrometry and testing the fractions for the effect on the expression of a Sonic Hh (Shh)–reporter gene in mammalian cell line (ShhLIGHT2), Khaliullina et al. found that endocannabinoids and related molecules inhibited Hh signaling. Blocking endocannabinoid catabolism using a pharmacological inhibitor of fatty acid amide hydrolase (FAAH) increased the inhibitory effects of several endocannabinoids either on SMO in Drosophila wing disc explants or on reporter activity in ShhLIGHT2 cells. Neither agonists nor antagonists of various known cannabinoid receptors repressed reporter activation in ShhLIGHT2 cells, and endocannabinoids reduced the activating effects of SMO agonist (SAG) in these cells, suggesting that endocannabinoids act directly on the Hh pathway, not by signaling downstream of the cannabinoid receptors. The addition of one of several endocannabinoids reduced the binding between SMO and a derivative of the SMO inhibitor cyclopamine in competitive binding assays. The findings identify a conserved mechanism of SMO inhibition and a new function for endocannabinoids.

H. Khaliullina, M. Bilgin, J. L. Sampaio, A. Shevchenko, S. Eaton, Endocannabinoids are conserved inhibitors of the Hedgehog pathway. Proc. Natl. Acad. Sci. U.S.A. 112, 3415–3420 (2015). [Abstract] [Full Text]