In a new study, under the leadership of Benoit Vanhollebeke, a researcher at the Free University of Brussels in Belgium, the researchers solved an important cell signaling mystery associated with Wnt signaling pathway. The results of the study were published online July 19, 2018 in the journal Science, entitled "A molecular mechanism for Wnt ligand-specific signaling."
Wnt is an ancient signaling pathway whose evolution seems to be traceable to the emergence of multicellular animals. It plays a key role in intercellular communication and controls several aspects of embryonic development and tissue homeostasis. When dysfunctional, Wnt signaling may be the origin of many diseases, especially several types of cancer. Given that this signaling pathway has 10 receptors and 19 ligands, and these receptors and ligands recognize each other, this signaling pathway appears to be extremely complex. How do vertebrate cells try to explain the many Wnt signals they encounter and trigger a sufficiently strong response? The mechanism behind this is exactly what these researchers have just discovered.
Previous studies have shown that two proteins expressed by brain endothelial cells, Gpr124 and Reck, are required for cerebrovascular development in response to Wnt7 ligands. Researchers then studied the mechanism of action of the Gpr124/Reck complex. Using genetic experiments, biophysical experiments, and zebrafish experiments, they confirmed that the Gpr124/Reck complex acts as a decoding module: Reck recognizes Wnt7 ligands, while Gpr124 exists to trigger what Wnt7 signaling required for transduction via frizzled receptors.
These findings will enable these researchers to better understand the Wnt signaling pathway and its various adjustments, making it possible to consider the development of new methods for treating diseases such as cancer or neurovascular diseases.
New advances in prostate cancer: a targeted therapy based on Wnt signaling pathway
A new generation of antiandrogens such as Xtandi from Pfizer and Astellas, and Zytiga from Johnson & Johnson, can improve the survival rate of metastatic castration-resistant prostate cancer (mCRPC). Recently, however, a multidisciplinary team from New York University has synthesized a new compound that is expected to further improve the treatment of the disease.
Scientists have been exploring new ways to treat prostate cancer, including the Wnt signaling pathway, which is mutated in about 20% of mCRPC cases. Wnt activation leads to the accumulation of beta-catenin, which binds to the T cell factor (TCF) transcription factor and triggers genes that promote cell proliferation. Activation of these genes is critical for early development of prostate tissue, but they may also cause cancer in adulthood. However, drug discovery for this pathway remains unclear.
In response to the Wnt signaling pathway and the interaction of beta-catenin and TCF, the New York University team believes that small molecules are not suitable for protein-protein binding surfaces because these surfaces are usually broad and flat; instead, the new compounds synthesized by them are very suitable, which is interposed between small molecules and macromolecular biologics and is called a peptidomimetic. These protein-like compounds have a structure similar to that of peptides, but there are significant differences in function. Because the peptidomimetic is large enough and its structure is resistant to proteolysis, it is expected to be a new therapy for targeting the Wnt signaling pathway.
Regarding the synthesis of this compound, the researchers explained that they folded a linear peptidomimetic into a 3D ring structure and "stacked" it so that it could block the docking site normally used by TCF. A new generation of computer simulation tools gives the team an early understanding of how this cyclic peptidomimetic fits its protein targets.
The team found that in cell culture experiments, this cyclic peptidomimetic reduced prostate cancer cell growth by 95% at 22 days compared to untreated cells. In contrast, treatment of cells with unmodified peptidomimetic only reduced cancer cell growth by 40%. In addition, they also reduce androgen signaling. The researchers believe that they may have dual anticancer effects.
The research team hopes to prove the role of this new compound in living animals, so they chose zebrafish. These zebrafish have rare Wnt activating mutations that cause the accumulation of beta-catenin and prevent the formation of the eye. In the experiment, the researchers found that cyclic peptidomimetic block the interaction of hyperactive β-catenin with TCF, allowing zebrafish to develop eye, an interaction similar to that affecting human prostate cancer.
These results have encouraged researchers to further test the therapeutic potential of this compound in a mouse model of prostate cancer. At the same time, they believe that the interaction of β-catenin with TCF may also be a good target for the treatment of other cancer types such as colon and breast cancer.
We look forward to the research team to bring more good news about prostate cancer treatment, and look forward to the day when humans can overcome prostate cancer.
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