The findings, reported by Vanderbilt University Medical Center researchers in the November issue of Nature Chemical Biology, suggest a fresh approach for developing therapeutics that target the pathway.
More than 90 percent of sporadic (non-inherited) colon cancers — the second deadliest type of cancer in the developed world — are caused by mutations that result in inappropriate activation of the Wnt (pronounced “wint”) signaling pathway. Blocking this pathway has been a desirable therapeutic target, but its complexity has made it difficult to determine which molecular participants to inhibit.
“There's no obvious target in the pathway where we could say, 'OK, if we inhibit the activity of this protein, that will inhibit Wnt signaling,'” said Ethan Lee, M.D., Ph.D., associate professor of Cell and Developmental Biology, Vanderbilt-Ingram Cancer Center researcher, and senior investigator of the current study.
Lee and his colleagues were interested in understanding the details of the Wnt pathway, which also plays an important role in early development. In frogs, loss of early Wnt signaling results in headless embryos; too much early Wnt signaling causes two heads to form.
“To me, that's really quite remarkable and says this pathway is biologically important,” Lee said.
To explore Wnt signaling at a biochemical level, Lee and his team developed frog embryo extracts and showed that this cell-free system retained many events of the Wnt signaling pathway. Using this system, they established a screening strategy to search for chemicals that modify Wnt signaling — with the goal of learning more about the biology of the pathway.
They found that pyrvinium, an FDA-approved anti-parasite drug, blocked Wnt signaling in the frog extracts.
They tested pyrvinium in cultured cells and in multiple animal models of early development (frogs, nematode worms, fruit flies) and demonstrated that in each case, pyrvinium blocked Wnt signaling. They also found that in cultured colon cancer cells, pyrvinium inhibited both Wnt signaling and cell proliferation.
To identify the target of pyrvinium, Lee and his colleagues combined four isolated proteins, all with known roles in the Wnt pathway. They found that pyrvinium increased the activity of one of the proteins, an enzyme called casein kinase 1alpha (CK1alpha).
The activation of a kinase — as a way to inhibit the Wnt signaling pathway — was unexpected, Lee said.
“The targeted cancer therapies that are being intensively studied right now are mostly kinase inhibitors,” he said. “It's intriguing to think that maybe there are certain kinases — like CK1alpha — that we can activate as targets for treating cancer.”
Pyrvinium stays in the gastrointestinal tract (to treat pinworms), so Lee is working with collaborators in the Vanderbilt Institute of Chemical Biology to develop new CK1alpha inhibitors. He is also collaborating with Pampee Young, M.D., Ph.D., associate professor of Pathology and Medicine, to study the Wnt pathway's role — and pyrvinium's effects — on cardiac repair after myocardial infarction.
“Our original goal in developing the screening strategy was to find compounds that would tell us something about the biology of the Wnt pathway,” Lee said. “It's an added bonus that these compounds could be useful therapeutic agents in heart disease or cancer.”
The frog embryo extract and screening strategy may also be applied to identifying compounds that modify other developmentally important signaling pathways, Lee added.
Curtis Thorne, Ph.D., is the first author of the Nature Chemical Biology paper. The Gastrointestinal Specialized Program of Research Excellence (GI SPORE) at Vanderbilt-Ingram, the American Cancer Society, and the National Institutes of Health supported the research.
Leigh MacMillan | EurekAlert!
Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory
How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy