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Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

Shih-Min A Huang1, Yuji M Mishina, Shanming Liu

  • 1Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.

Nature
|September 18, 2009
PubMed

Insights

A new molecule, XAV939, targets cancer by stabilizing axin, a key protein in the Wnt pathway. This promotes the degradation of beta-catenin, inhibiting cancer growth and offering new therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Drug Discovery

Background:

  • The Wnt pathway is crucial for cell development and is frequently dysregulated in cancers.
  • Beta-catenin stability is tightly controlled by the destruction complex, making it a cancer target.
  • Targeting the Wnt pathway is challenging due to limited druggable components.

Purpose of the Study:

  • To identify small molecules that inhibit beta-catenin-mediated transcription.
  • To elucidate the mechanism of action for novel Wnt pathway inhibitors.

Main Methods:

  • Chemical genetic screen to identify XAV939.
  • Quantitative chemical proteomics to identify XAV939 targets.
  • Analysis of axin protein homeostasis and degradation pathways.

Main Results:

  • XAV939 selectively inhibits beta-catenin transcription by stabilizing axin.
  • XAV939 inhibits tankyrase 1 and tankyrase 2, enzymes that promote axin degradation.
  • Tankyrase inhibition leads to increased axin levels and beta-catenin degradation via the ubiquitin-proteasome pathway.

Conclusions:

  • XAV939 provides a novel therapeutic strategy by targeting axin stability.
  • Inhibiting tankyrase offers a new approach for Wnt pathway-driven cancer therapy.
  • Understanding axin regulation opens new avenues for cancer treatment.

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