PUBLICATION
Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer
- Authors
- Qu, Y., Gharbi, N., Yuan, X., Olsen, J.R., Blicher, P., Dalhus, B., Brokstad, K.A., Lin, B., Øyan, A.M., Zhang, W., Kalland, K.H., Ke, X.
- ID
- ZDB-PUB-160804-18
- Date
- 2016
- Source
- Proceedings of the National Academy of Sciences of the United States of America 113(33): 9339-44 (Journal)
- Registered Authors
- Keywords
- SHPRH, asymmetric cell division, axitinib, β-catenin
- MeSH Terms
-
- Animals
- 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
- beta Catenin/physiology*
- PubMed
- 27482107 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Qu, Y., Gharbi, N., Yuan, X., Olsen, J.R., Blicher, P., Dalhus, B., Brokstad, K.A., Lin, B., Øyan, A.M., Zhang, W., Kalland, K.H., Ke, X. (2016) Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer. Proceedings of the National Academy of Sciences of the United States of America. 113(33):9339-44.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping