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

Autor: Ariel Ruiz i Altaba, Christophe Mas, Jens Mueller, Monika Kuciak, Isabel Borges, Chandan Seth, Arwen Conod, Karsten Siems
Rok vydání: 2016
Předmět:
0301 basic medicine
Carcinogenesis
Colorectal cancer
Nude
Cancer Treatment
lcsh:Medicine
Gene Expression
TCF/LEF family
Biochemistry
Epigenesis
Genetic
Histones
Mice
Cell Signaling
Animal Cells
Cancer Stem Cells
Medicine and Health Sciences
Homeostasis
ddc:576.5
lcsh:Science
Wnt Signaling Pathway
WNT Signaling Cascade
Tissue homeostasis
Tumor
Multidisciplinary
Stem Cells
Wnt signaling pathway
Neoplastic Stem Cells/cytology
Signaling Cascades
Chromatin
Colonic Neoplasms/metabolism
Oncology
Colonic Neoplasms
Neoplastic Stem Cells
Epigenetics
Female
Chromatin/chemistry
Cellular Types
Signal transduction
TCF Transcription Factors
Research Article
Signal Transduction
Histones/chemistry
Mice
Nude
Withanolides/chemistry
Library Screening
Biology
Research and Analysis Methods
Cell Line
03 medical and health sciences
Genetic
TCF Transcription Factors/metabolism
Wnt Proteins/metabolism
Cancer stem cell
Cell Line
Tumor
Wnt Signaling Pathway/drug effects
DNA-binding proteins
Genetics
medicine
Animals
Humans
Molecular Biology Techniques
Molecular Biology
Withanolides
Colorectal Cancer
Molecular Biology Assays and Analysis Techniques
Ivermectin
lcsh:R
HEK 293 cells
Cancers and Neoplasms
Biology and Life Sciences
Proteins
Epistasis
Genetic
Cell Biology
medicine.disease
Wnt Proteins
HEK293 Cells
030104 developmental biology
Ivermectin/chemistry
Cancer cell
Epistasis
Cancer research
lcsh:Q
Neoplasm Transplantation
Epigenesis
Zdroj: PLoS ONE
PLOS ONE, Vol. 11, No 12 (2016) P. e0168170
PLoS ONE, Vol 11, Iss 12, p e0168170 (2016)
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0168170
Popis: 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.
Databáze: OpenAIRE
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