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!
Molecular Force Sensors
20.09.2017 | Max-Planck-Institut für Biochemie
Foster tadpoles trigger parental instinct in poison frogs
20.09.2017 | Veterinärmedizinische Universität Wien
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...
Pathogenic bacteria are becoming resistant to common antibiotics to an ever increasing degree. One of the most difficult germs is Pseudomonas aeruginosa, a...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
20.09.2017 | Life Sciences
20.09.2017 | Power and Electrical Engineering
20.09.2017 | Physics and Astronomy