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

Mueller, Jens
Siems, Karsten
Published in PLOS ONE. 2016, vol. 11, no. 12, e0168170
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.
Keywords AnimalsCell LineTumorChromatin/chemistryColonic Neoplasms/metabolismEpigenesisGeneticEpistasisGeneticFemaleHEK293 CellsHistones/chemistryHomeostasisHumansIvermectin/chemistryMiceMiceNudeNeoplasm TransplantationNeoplastic Stem Cells/cytologySignal TransductionTCF Transcription Factors/metabolismWithanolides/chemistryWnt Proteins/metabolismWnt Signaling Pathway/drug effects
PMID: 27973612
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Research group Stemness in developpment and disease: Signalling, reprogramming and mechanisms of metastases (776)
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SETH, Chandan et al. Long-Lasting WNT-TCF Response Blocking and Epigenetic Modifying Activities of Withanolide F in Human Cancer Cells. In: PLOS ONE, 2016, vol. 11, n° 12, p. e0168170. doi: 10.1371/journal.pone.0168170 https://archive-ouverte.unige.ch/unige:100251

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Deposited on : 2017-12-13

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