Format

Send to

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

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

Author information

1
Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; Department of Microbiology, Haukeland University Hospital, N-5021 Bergen, Norway;
2
Institute of Marine Biology, University of Bergen, N-5020 Bergen, Norway;
3
Department of Phytochemistry, College of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China;
4
Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway;
5
Department of Medical Biochemistry, Institute for Clinical Medicine, University of Oslo, N-0424 Oslo, Norway;
6
Department of Medical Biochemistry, Institute for Clinical Medicine, University of Oslo, N-0424 Oslo, Norway; Department of Microbiology, Oslo University Hospital HF, Rikshospitalet, N-0424 Oslo, Norway;
7
Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway;
8
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003 People's Republic of China;
9
Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; Department of Microbiology, Haukeland University Hospital, N-5021 Bergen, Norway; Centre for Cancer Biomarkers, University of Bergen, N-5021 Bergen, Norway Xisong.Ke@uib.no Kalland@uib.no.
10
Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; Xisong.Ke@uib.no Kalland@uib.no.

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.

KEYWORDS:

SHPRH; asymmetric cell division; axitinib; β-catenin

PMID:
27482107
PMCID:
PMC4995957
DOI:
10.1073/pnas.1604520113
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central Icon for Norwegian BIBSYS system
Loading ...
Support Center