A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice

被引:277
作者
Waaler, Jo [1 ,3 ]
Machon, Ondrej [1 ,3 ,7 ]
Tumova, Lucie [7 ]
Dinh, Huyen [1 ,3 ]
Korinek, Vladimir [7 ]
Wilson, Steven Ray [2 ]
Paulsen, Jan Erik [4 ]
Pedersen, Nina Marie [5 ]
Eide, Tor J. [6 ]
Machonova, Olga [1 ,3 ,7 ]
Gradl, Dietmar [8 ]
Voronkov, Andrey [1 ,3 ]
von Kries, Jens Peter [9 ]
Krauss, Stefan [1 ,3 ]
机构
[1] Oslo Univ Hosp, SFI CAST Biomed Innovat Ctr, Unit Cell Signaling, N-0349 Oslo, Norway
[2] Univ Oslo, Dept Chem, Oslo, Norway
[3] Ctr Mol Biol & Neurosci, N-0317 Oslo, Norway
[4] Norwegian Sch Vet Sci, Dept Food Safety & Infect Biol, Oslo, Norway
[5] Norwegian Radium Hosp, Inst Canc Res, Dept Biochem, Stem Cell Innovat Ctr, Oslo, Norway
[6] Oslo Univ Hosp, Rikshosp, Dept Pathol, N-0349 Oslo, Norway
[7] Acad Sci Czech Republic, Inst Mol Genet, Prague, Czech Republic
[8] KIT, Inst Zool, Karlsruhe, Germany
[9] FMP, Leibniz Inst Mol Pharmakol, Berlin, Germany
关键词
CANCER STEM-CELLS; SMALL-MOLECULE INHIBITOR; BETA-CATENIN; COLORECTAL-CANCER; PATHWAY; COMPLEX; AXIN; PHOSPHORYLATION; ANTAGONISTS; BINDING;
D O I
10.1158/0008-5472.CAN-11-3336
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Increased nuclear accumulation of beta-catenin, a mediator of canonical Wnt signaling, is found in numerous tumors and is frequently associated with tumor progression and metastasis. Inhibition of Wnt/beta-catenin signaling therefore is an attractive strategy for anticancer drugs. In this study, we have identified a novel small molecule inhibitor of the beta-catenin signaling pathway, JW55, that functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2), regulators of the beta-catenin destruction complex. Inhibition of TNKS1/2 poly(ADP-ribosyl) ation activity by JW55 led to stabilization of AXIN2, a member of the beta-catenin destruction complex, followed by increased degradation of beta-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 beta-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/beta-catenin signaling through inhibiting the PARP domain of TNKS1/2. Cancer Res; 72(11); 2822-32. (C)2012 AACR.
引用
收藏
页码:2822 / 2832
页数:11
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