Article

Hedgehog signaling controls many crucial processes during development. For instance, it regulates segmentation in insects, and in vertebrates Hedgehog is crucial for the establishment of a left-right symmetry.  In adult organisms, it also plays an important role in tissue regeneration. Hedgehog signaling occurs through activation of the protein Smoothened. Hyperactivation of this protein underlies many tumors. We seem to have a set of compounds produced from within our body that can repress Smoothened signaling. However, the identity of these molecules was unknown. Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), using biochemical fractionation and lipidomics, have now succeeded in identifying the compounds as endocannabinoids. This suggests a new molecular starting point for designing drugs to block Hedgehog signaling. Endocannabinoids mimic the effects that cannabinoids have – these substances can be found in the Cannabis plant. (PNAS Early Edition, 2 March 2015)

Hedgehog signaling is crucial during embryonic development and adult tissue homeostasis, but it can become problematic when it is inappropriately activated: If it does not remain switched off, it can, via the activation of Smoothened, trigger the development of many tumors. This is why modulating Smoothened activity has been studied as a therapeutic approach in clinical research – and has shown quite some promise. But little was known about the small molecules produced from within our body that are required to inhibit the protein in vivo.

Suzanne Eaton’s research team now identified a set of compounds that repress Hedgehog signaling: Experiments in fruit flies first suggested that such a compound must exist in lipoprotein particles. So the researchers purified the compounds from human very-low-density lipoprotein using human tissue culture assays. Using biochemical fractionation and lipid mass spectrometry, they identified the compounds as endocannabinoids and showed that their repressive effects on the Hedgehog pathway have been preserved across phyla from flies to humans. Endocannabinoids got their name because they are the endogenous compounds whose effects are mimicked by the cannabinoids found in Cannabis. Their effects on the body are complex and they act through several different kinds of cellular receptors, but it had never been suspected that they could change the activity of the Hedgehog pathway.

Smoking pot to cure cancer?

The potential of marijuana as a drug in cancer therapy has been investigated for some time. „Our findings do not suggest that smoking pot is a way to cure cancer“, says MPI-CBG group leader Suzanne Eaton. But understanding that cannabinoids are Smoothened inhibitors could help guide the development of even more potent molecules with anti-tumor activity. There are already drugs that target Smoothened that are beginning to be used in the clinic. They have powerful effects on some tumors, but not others.  Even when they work, tumors often develop resistance to them. „So we believe it is important to have a second class of compounds that works against Smoothened in a slightly different way“, says Eaton.

"Because the Hedgehog signaling pathway is critical for mammalian tissue regeneration and repair, our findings actually raise additional concerns about the long-term effects of cannabis consumption. One should consider whether smoking pot might interfere with some of these normal physiological functions of the Hedgehog pathway".

Hedgehog has been a research focus of Suzanne Eaton’s and kept her lab busy for many years. Just recently, her research team explained how fruit flies use Hedgehog to slow down growth during development in scarce situations. Also they showed that Hedgehog travels far distances between organs and not just within tissues.