A PROTAC peptide induces durable B-catenin degradation and suppresses Wnt-dependent intestinal cancer.
Aberrant activation of Wnt/B-catenin signaling has been associated with the onset and progression of many types of tumors and thus B-catenin represents one attractive intracellular target for cancer therapy. Based on the Axin-derived peptide that binds to B-catenin, two stapled peptides SAHPA1 and xStAx were reported to enhance or impair ... Wnt/B-catenin signaling, respectively. In this study, we designed PROTACs (proteolysis targeting chimeras) by coupling SAHPA1 or xStAx with the VHL ligand to achieve efficient B-catenin degradation. The obtained xStAx-VHLL sustained B-catenin degradation and manifested strong inhibition of Wnt signaling in cancer cells and in APC organoids. Furthermore, xStAx-VHLL could effectively restrain tumor formation in BALB/C nude mice, and diminish the existing tumors in APC mice. More importantly, xStAx-VHLL could potently inhibit the survival of colorectal cancer patient-derived organoids. These findings suggest that xStAx-VHLL exhibits the ability of cancer prevention and cure, highlighting the potential of B-catenin degrader PROTACs as a new class of promising anticancer agent.
Mesh Terms:
Antineoplastic Agents, Cell Line, Tumor, HEK293 Cells, Humans, Ligands, Lymphoma, Large B-Cell, Diffuse, Peptide Hydrolases, Protein Binding, Proteolysis, Proto-Oncogene Proteins c-bcl-6, Quinolones, Thalidomide, Ubiquitin-Protein Ligases
Antineoplastic Agents, Cell Line, Tumor, HEK293 Cells, Humans, Ligands, Lymphoma, Large B-Cell, Diffuse, Peptide Hydrolases, Protein Binding, Proteolysis, Proto-Oncogene Proteins c-bcl-6, Quinolones, Thalidomide, Ubiquitin-Protein Ligases
Cell Discov
Date: Jun. 19, 2020
PubMed ID: 32550000
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