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Sci Rep. 2016 Jul 19;6:29868. doi: 10.1038/srep29868.

Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation.

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Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Box 595, Biomedical Center, SE-751 24 Uppsala, Sweden.
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, Biomedical Center, SE-751 23 Uppsala, Sweden.
Department of Biochemistry, University of Crete Medical School, 71003 Heraklion, Crete, Greece.
Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.


Plasticity in epithelial tissues relates to processes of embryonic development, tissue fibrosis and cancer progression. Pharmacological modulation of epithelial transitions during disease progression may thus be clinically useful. Using human keratinocytes and a robotic high-content imaging platform, we screened for chemical compounds that reverse transforming growth factor β (TGF-β)-induced epithelial-mesenchymal transition. In addition to TGF-β receptor kinase inhibitors, we identified small molecule epithelial plasticity modulators including a naturally occurring hydroxysterol agonist of the liver X receptors (LXRs), members of the nuclear receptor transcription factor family. Endogenous and synthetic LXR agonists tested in diverse cell models blocked α-smooth muscle actin expression, myofibroblast differentiation and function. Agonist-dependent LXR activity or LXR overexpression in the absence of ligand counteracted TGF-β-mediated myofibroblast terminal differentiation and collagen contraction. The protective effect of LXR agonists against TGF-β-induced pro-fibrotic activity raises the possibility that anti-lipidogenic therapy may be relevant in fibrotic disorders and advanced cancer.

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