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

PLoS One. 2016 Dec 14;11(12):e0168170. doi: 10.1371/journal.pone.0168170. eCollection 2016.

Abstract

The WNT-TCF signaling pathway participates in adult tissue homeostasis and repair, and is hyperactive in a number of human diseases including cancers of the colon. Whereas to date there are no antagonists approved for patient use, a potential problem for their sustained use is the blockade of WNT signaling in healthy tissues, thus provoking potentially serious co-lateral damage. Here we have screened a library of plant and microorganism small molecules for novel WNT signaling antagonists and describe withanolide F as a potent WNT-TCF response blocker. This steroidal lactone inhibits TCF-dependent colon cancer xenograft growth and mimics the effects of genetic blockade of TCF and of ivermectin, a previously reported WNT-TCF blocker. However, withanolide F is unique in that it imposes a long-lasting repression of tumor growth, WNT-TCF targets and cancer stem cell clonogenicity after drug treatment. These findings are paralleled by its modulation of chromatin regulators and its alteration of overall H3K4me1 levels. Our results open up the possibility to permanently repress essential signaling responses in cancer cells through limited treatments with small molecules.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Chromatin / chemistry
  • Colonic Neoplasms / metabolism
  • Epigenesis, Genetic*
  • Epistasis, Genetic
  • Female
  • HEK293 Cells
  • Histones / chemistry
  • Homeostasis
  • Humans
  • Ivermectin / chemistry
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / cytology
  • Signal Transduction
  • TCF Transcription Factors / metabolism*
  • Withanolides / chemistry*
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway / drug effects*

Substances

  • Chromatin
  • Histones
  • TCF Transcription Factors
  • Withanolides
  • Wnt Proteins
  • Ivermectin

Grants and funding

This work was funded by European Union ITN grants CAPPELLA and HEALING to ARA (Université de Genève) and Analyticon Discovery, and by the Swiss Cancer League, National Swiss Science Foundation and the Département d’Instruction Publique de Genève to ARA. Analyticon Discovery Gmbh provided support in the form of funds for small molecule sample preparation and analyses and salaries for authors JM and KS. Analyticon was in charge of providing extracts and small molecules and the discussion of the initial screen and project, as well as ongoing discussion on small molecules and their effects. As a company, it did not have additional roles in data collection and analysis, decision to publish, or preparation of the manuscript other than JM and KS providing insight and comments on the ms. The specific roles of these authors are articulated in the ‘author contributions’ section.