A novel tankyrase inhibitor decreases canonical Wnt signaling in colon carcinoma cells and reduces tumor growth in conditional APC mutant mice

Cancer Res. 2012 Jun 1;72(11):2822-32. doi: 10.1158/0008-5472.CAN-11-3336. Epub 2012 Mar 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axin Protein / analysis
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Genes, APC / physiology*
  • Humans
  • Mice
  • Mice, Knockout
  • Tankyrases / antagonists & inhibitors*
  • Wnt Signaling Pathway / drug effects*
  • Xenopus laevis
  • beta Catenin / chemistry
  • beta Catenin / physiology
  • para-Aminobenzoates* / pharmacology

Substances

  • Axin Protein
  • Axin2 protein, mouse
  • Enzyme Inhibitors
  • JW55 compound
  • beta Catenin
  • para-Aminobenzoates
  • Tankyrases
  • TNKS protein, human