Long-Lasting WNT-TCF Response Blocking and Epigenetic Modifying Activities of Withanolide F in Human Cancer Cells

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Chandan Seth1, Christophe Mas1, Arwen Conod1

  • 1Department of Medical Genetics and Development, CMU, 1 rue Michel Servet, Geneva, Switzerland.

Plos One
|December 16, 2016
PubMed

Insights

A novel plant-derived compound, withanolide F, effectively blocks WNT-TCF signaling in colon cancer. This discovery offers a potential for long-lasting tumor repression with limited treatment, minimizing side effects in healthy tissues.

Area of Science:

  • Molecular Biology
  • Oncology
  • Pharmacology

Background:

  • The WNT-TCF signaling pathway is crucial for tissue homeostasis but is aberrantly activated in diseases like colon cancer.
  • Current WNT signaling antagonists face challenges due to potential side effects from blocking the pathway in healthy tissues.

Purpose of the Study:

  • To identify novel small molecules that antagonize WNT-TCF signaling.
  • To evaluate the therapeutic potential of identified compounds, focusing on efficacy and long-term effects in cancer models.

Main Methods:

  • Screening of plant and microorganism small molecule libraries for WNT-TCF antagonists.
  • Inhibition assays using colon cancer xenografts and cancer stem cell models.
  • Analysis of chromatin regulator modulation and H3K4me1 levels.

Main Results:

  • Withanolide F was identified as a potent WNT-TCF response blocker.
  • Withanolide F inhibited TCF-dependent colon cancer xenograft growth and cancer stem cell clonogenicity.
  • The compound induced long-lasting repression of tumor growth and WNT-TCF targets, modulating chromatin regulators and H3K4me1 levels.

Conclusions:

  • Withanolide F represents a promising WNT-TCF antagonist with unique long-lasting effects.
  • Limited treatments with withanolide F may offer a strategy for permanent repression of signaling pathways in cancer cells.
  • This approach could overcome the limitations of current WNT signaling inhibitors, reducing collateral damage to healthy tissues.

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