Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer

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-c...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2016-08, Vol.113 (33), p.9339-9344
Main Authors: Qu, Yi, Gharbi, Naouel, Yuan, Xing, Olsen, Jan Roger, Blicher, Pernille, Dalhus, Bjørn, Brokstad, Karl A., Lin, Biaoyang, Øyan, Anne Margrete, Zhang, Weidong, Kalland, Karl-Henning, Ke, Xisong
Format: Article
Language:English
Subjects:
Animals
Axitinib
beta Catenin - physiology
Biological Sciences
Cell Division - drug effects
DNA Helicases - physiology
Glycogen Synthase Kinase 3 beta - physiology
HCT116 Cells
Humans
Imidazoles - pharmacology
Indazoles - pharmacology
Male
Mice
Mice, Inbred C57BL
Neoplasms - pathology
Protein Kinase Inhibitors - pharmacology
Regeneration - drug effects
Ubiquitin-Protein Ligases - physiology
Wnt Signaling Pathway - drug effects
Zebrafish
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1604520113