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Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer
Yi Qu1, Naouel Gharbi2, Xing Yuan3
1Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; Department of Microbiology, Haukeland University Hospital, N-5021 Bergen, Norway;
Abstract:
Oncogenic mutations of the Wnt (wingless)/β-catenin pathway are frequently observed in major cancer types. Thus far, however, no therapeutic agent targeting Wnt/β-catenin signaling is available for clinical use. Here we demonstrate that axitinib, a clinically approved drug, strikingly blocks Wnt/β-catenin signaling in cancer cells, zebrafish, and Apc(min/+) mice. Notably, axitinib dramatically induces Wnt asymmetry and nonrandom DNA segregation in cancer cells by promoting nuclear β-catenin degradation independent of the GSK3β (glycogen synthase kinase3β)/APC (adenomatous polyposis coli) complex. Using a DARTS (drug affinity-responsive target stability) assay coupled to 2D-DIGE (2D difference in gel electrophoresis) and mass spectrometry, we have identified the E3 ubiquitin ligase SHPRH (SNF2, histone-linker, PHD and RING finger domain-containing helicase) as the direct target of axitinib in blocking Wnt/β-catenin signaling. Treatment with axitinib stabilizes SHPRH and thereby increases the ubiquitination and degradation of β-catenin. Our findings suggest a previously unreported mechanism of nuclear β-catenin regulation and indicate that axitinib, a clinically approved drug, would provide therapeutic benefits for cancer patients with aberrant nuclear β-catenin activation.
Insights
Axitinib, an approved drug, effectively inhibits Wnt/β-catenin signaling crucial for cancer growth. It targets SHPRH, promoting β-catenin degradation and offering a new therapeutic strategy for various cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Wnt/β-catenin pathway mutations are common in many cancers.
- Targeting this pathway is a key therapeutic goal.
- No specific Wnt/β-catenin inhibitors are currently approved for clinical use.
Purpose of the Study:
- To identify a clinically approved drug that can inhibit Wnt/β-catenin signaling.
- To elucidate the mechanism by which this drug affects the pathway.
- To explore its potential as a cancer therapeutic.
Main Methods:
- Drug screening using cancer cells, zebrafish, and Apc(min/+) mice models.
- Assessing Wnt/β-catenin signaling activity.
- Utilizing DARTS assay, 2D-DIGE, and mass spectrometry to identify drug targets.
- Investigating protein interactions and degradation pathways.
Main Results:
- Axitinib, an approved drug, significantly inhibits Wnt/β-catenin signaling.
- Axitinib promotes nuclear β-catenin degradation independently of the GSK3β/APC complex.
- SHPRH was identified as the direct target of axitinib, stabilizing it and increasing β-catenin ubiquitination and degradation.
Conclusions:
- Axitinib offers a novel therapeutic approach for cancers with activated Wnt/β-catenin signaling.
- The findings reveal a new mechanism for regulating nuclear β-catenin.
- Axitinib's ability to target SHPRH provides a potential treatment strategy for patients with aberrant Wnt signaling.
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