A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer

• Published in: Cell discovery Vol. 6; no. 1; p. 35
• Main Authors: Liao, Hongwei, Li, Xiang, Zhao, Lianzheng, Wang, Yalong, Wang, Xiaodan, Wu, Ye, Zhou, Xin, Fu, Wei, Liu, Lei, Hu, Hong-Gang, Chen, Ye-Guang
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 09.06.2020; Springer Nature B.V
• Subjects: 631/67/1059/153; 631/67/1059/602; Adenomatous polyposis coli; Biomedical and Life Sciences; Cancer; Cell Biology; Cell Culture; Cell Cycle Analysis; Cell Physiology; Chimeras; Colorectal cancer; Colorectal carcinoma; Degradation; Intestine; Life Sciences; Organoids; Peptides; Prostate cancer; Proteolysis; Stem Cells; Tumors; Wnt protein; β-Catenin
• ISSN: 2056-5968; 2056-5968
• DOI: 10.1038/s41421-020-0171-1

Aberrant activation of Wnt/β-catenin signaling has been associated with the onset and progression of many types of tumors and thus β-catenin represents one attractive intracellular target for cancer therapy. Based on the Axin-derived peptide that binds to β-catenin, two stapled peptides SAHPA1 and xStAx were reported to enhance or impair Wnt/β-catenin signaling, respectively. In this study, we designed PROTACs (proteolysis targeting chimeras) by coupling SAHPA1 or xStAx with the VHL ligand to achieve efficient β-catenin degradation. The obtained xStAx-VHLL sustained β-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 min/+ 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 β-catenin degrader PROTACs as a new class of promising anticancer agent.