title: A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice.
abstract: Increased nuclear accumulation of β-catenin, a mediator of canonical Wnt signaling, is found in numerous tumors and is frequently associated with tumor progression and metastasis. Inhibition of Wnt/β-catenin signaling therefore is an attractive strategy for anticancer drugs. In this study, we have identified a novel small molecule inhibitor of the β-catenin signaling pathway, JW55, that functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2), regulators of the β-catenin destruction complex. Inhibition of TNKS1/2 poly(ADP-ribosyl)ation activity by JW55 led to stabilization of AXIN2, a member of the β-catenin destruction complex, followed by increased degradation of β-catenin. In a dose-dependent manner, JW55 inhibited canonical Wnt signaling in colon carcinoma cells that contained mutations in either the APC (adenomatous polyposis coli) locus or in an allele of β-catenin. In addition, JW55 reduced XWnt8-induced axis duplication in Xenopus embryos and tamoxifen-induced polyposis formation in conditional APC mutant mice. Together, our findings provide a novel chemotype for targeting canonical Wnt/β-catenin signaling through inhibiting the PARP domain of TNKS1/2.
authors.affiliation: Oslo University Hospital, SFI-CAST Biomedical Innovation Center, Unit for Cell Signaling, Forskningsparken, Gaustadalleen and Center for Molecular Biology and Neuroscience, Oslo, Norway. jo.waaler@rr-research.no
authors.forename: Jo
authors.initials: J
authors.lastname: Waaler
authors.forename: Ondrej
authors.initials: O
authors.lastname: Machon
authors.forename: Lucie
authors.initials: L
authors.lastname: Tumova
authors.forename: Huyen
authors.initials: H
authors.lastname: Dinh
authors.forename: Vladimir
authors.initials: V
authors.lastname: Korinek
authors.forename: Steven Ray
authors.initials: SR
authors.lastname: Wilson
authors.forename: Jan Erik
authors.initials: JE
authors.lastname: Paulsen
authors.forename: Nina Marie
authors.initials: NM
authors.lastname: Pedersen
authors.forename: Tor J
authors.initials: TJ
authors.lastname: Eide
authors.forename: Olga
authors.initials: O
authors.lastname: Machonova
authors.forename: Dietmar
authors.initials: D
authors.lastname: Gradl
authors.forename: Andrey
authors.initials: A
authors.lastname: Voronkov
authors.forename: Jens Peter
authors.initials: JP
authors.lastname: von Kries
authors.forename: Stefan
authors.initials: S
authors.lastname: Krauss
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000032:analysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D017491:Genes, APC / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D038501:Tankyrases / Q000037:antagonists & inhibitors*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D014982:Xenopus laevis; D051176:beta Catenin / Q000737:chemistry / Q000502:physiology; D062366:para-Aminobenzoates / Q000494:pharmacology
chemical_list: D060466:Axin Protein; D004791:Enzyme Inhibitors; D038501:Tankyrases; D051176:beta Catenin; D062366:para-Aminobenzoates; C111729:Axin2 protein, mouse; C000613569:JW55 compound; C418109:TNKS protein, human