title: Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer.
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.
authors.affiliation: Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; Department of Microbiology, Haukeland University Hospital, N-5021 Bergen, Norway;
authors.forename: Yi
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Institute of Marine Biology, University of Bergen, N-5020 Bergen, Norway;
authors.forename: Naouel
authors.initials: N
authors.lastname: Gharbi
authors.affiliation: Department of Phytochemistry, College of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China;
authors.forename: Xing
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway;
authors.forename: Jan Roger
authors.initials: JR
authors.lastname: Olsen
authors.affiliation: Department of Medical Biochemistry, Institute for Clinical Medicine, University of Oslo, N-0424 Oslo, Norway;
authors.forename: Pernille
authors.initials: P
authors.lastname: Blicher
authors.affiliation: 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;
authors.forename: Bjørn
authors.initials: B
authors.lastname: Dalhus
authors.affiliation: 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;
authors.forename: Karl A
authors.initials: KA
authors.lastname: Brokstad
authors.affiliation: 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;
authors.forename: Biaoyang
authors.initials: B
authors.lastname: Lin
authors.affiliation: Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway;
authors.forename: Anne Margrete
authors.initials: AM
authors.lastname: Øyan
authors.affiliation: Department of Phytochemistry, College of Pharmacy, Second Military Medical University, Shanghai 200433, People's Republic of China;
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Karl-Henning
authors.initials: KH
authors.lastname: Kalland
authors.affiliation: Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway; Xisong.Ke@uib.no Kalland@uib.no.
authors.forename: Xisong
authors.initials: X
authors.lastname: Ke
mesh_terms: D000818:Animals; D000077784:Axitinib; D002455:Cell Division / Q000187:drug effects*; D004265:DNA Helicases / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta / Q000502:physiology; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012038:Regeneration / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D015027:Zebrafish; D051176:beta Catenin / Q000502:physiology*
chemical_list: D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D000077784:Axitinib; C516226:SHPRH protein, human; D044767:Ubiquitin-Protein Ligases; D000071679:Glycogen Synthase Kinase 3 beta; D004265:DNA Helicases
keywords: SHPRH; asymmetric cell division; axitinib; β-catenin