RRC ID 49679
Author Qu Y, Gharbi N, Yuan X, Olsen JR, Blicher P, Dalhus B, Brokstad KA, Lin B, Øyan AM, Zhang W, Kalland KH, Ke X.
Title Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer.
Journal Proc Natl Acad Sci U S A
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.
Volume 113(33)
Pages 9339-44
Published 2016-8-16
DOI 10.1073/pnas.1604520113
PII 1604520113
PMID 27482107
PMC PMC4995957
MeSH 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*
IF 9.412
Times Cited 33
Zebrafish Tg(6xTcf/LefBS-miniP:d2EGFP)