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

Proc Natl Acad Sci U S A. 2016 Aug 16;113(33):9339-44. doi: 10.1073/pnas.1604520113. Epub 2016 Aug 1.


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.

Keywords: SHPRH; asymmetric cell division; axitinib; β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axitinib
  • 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*


  • Imidazoles
  • Indazoles
  • Protein Kinase Inhibitors
  • beta Catenin
  • Axitinib
  • SHPRH protein, human
  • Ubiquitin-Protein Ligases
  • Glycogen Synthase Kinase 3 beta
  • DNA Helicases