Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin
Open accessAbstract
Aberrant activation of signaling by the Wnt pathway is strongly implicated in the onset and progression of numerous types of cancer. Owing to the persistent dependence of these tumors on Wnt signaling for growth and survival, inhibition of this pathway is considered an attractive mechanism-based therapeutic approach. Oncogenic activation of Wnt signaling can ensue from a variety of distinct aberrations in the signaling pathway, but most share the common feature of causing increased cellular levels of β-catenin by interfering with its constitutive degradation. β-Catenin serves as a central hub in Wnt signaling by engaging in crucial protein–protein interactions with both negative and positive effectors of the pathway. Direct interference with these protein–protein interactions is a biologically compelling approach toward suppression of β-catenin hyperactivity, but such interactions have proven intransigent with respect to small-molecule targeting. Hence β-catenin remains an elusive target for translational cancer therapy. Here we report the discovery of a hydrocarbon-stapled peptide that directly targets β-catenin and interferes with its ability to serve as a transcriptional coactivator for T-cell factor (TCF) proteins, the downstream transcriptional regulators of the Wnt pathway.
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SAHPA1 and xStAx are capable of penetrating the cell membrane and binding with β-catenin.
“Both SAHPA1 and xStAx are capable of penetrating the cell membrane and binding with β-catenin.”
From A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer (2020) · cites this paper as [14]
The Results (Fig. 3) report cellular uptake of StAx peptides and their binding to β-catenin, supporting that part of the claim. The paper does not identify a peptide called xStAx or address SAHPA1, so it does not establish the claim for both named peptides. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSAHPA1 activates Wnt/β-catenin signaling.
“SAHPA1 was shown to activate Wnt/β-catenin signaling, while xStAx inhibited it13,14.”
From A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer (2020) · cites this paper as [14]
xStAx inhibits Wnt/β-catenin signaling.
“SAHPA1 was shown to activate Wnt/β-catenin signaling, while xStAx inhibited it13,14.”
From A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer (2020) · cites this paper as [14]
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- Authors
- Grossmann, T. N., Yeh, J. T.-H., Bowman, B. R., Chu, Q., Moellering, R. E., & Verdine, G. L.
- Affiliations
- Departments of aStem Cell and Regenerative Biology,
- Harvard University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-10-15
- Volume
- 109
- Issue
- 44
- Pages
- 17942-17947
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3497784
- OpenAlex
- W2165956359
- Cited by
- 268
- References
- 35
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 26 · 2023: 14 · 2022: 17 · 2021: 29 · 2020: 29 · 2019: 16 · 2018: 16 · 2017: 17 · 2016: 14 · 2015: 20 · 2014: 31 · 2013: 11 · 2012: 1
- FWCI
- 7.70
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- VU Research Portal (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- Wnt signaling, β-catenin, hydrocarbon-stapled peptides, protein-protein interaction, T-cell factor, transcriptional coactivator, cancer therapy, small molecule inhibitors, β-catenin degradation
- MeSH terms
- Amino Acid Sequence, HeLa Cells, Humans, Molecular Sequence Data, Oncogenes, Transcription, Genetic, Signal Transduction, Wnt Proteins, beta Catenin
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