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

Hongwei LiaoXiang LiLianzheng ZhaoYalong WangXiaodan WangYe WuXin ZhouWei FuSanling LiuHong-Gang HuYe-Guang Chen
Published in: Cell discovery (2020)
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.
Keyphrases
  • cell proliferation
  • epithelial mesenchymal transition
  • cancer therapy
  • stem cells
  • signaling pathway
  • type diabetes
  • drug delivery
  • adipose tissue
  • skeletal muscle
  • metabolic syndrome
  • climate change