Abstract
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.
Highlights
Signalling cascade that involves Smad proteins and various branches of protein kinases, including mitogen activated protein kinases (MAPKs) and small GTPases, which coordinately affect gene expression to manifest the biological effects of this growth factor[5]
The choice of fibronectin is in agreement with a recently reported high-content screen preformed in a mammary epithelial cell model, which identified a set of kinase inhibitors affecting the EMT18
Based on the robust pharmacology of liver X receptor (LXR) ligands observed in our screening, we focused on understanding their impact on myofibroblast differentiation
Summary
Signalling cascade that involves Smad proteins and various branches of protein kinases, including mitogen activated protein kinases (MAPKs) and small GTPases, which coordinately affect gene expression to manifest the biological effects of this growth factor[5]. Prolonged TGF-βactivity in a given epithelial tissue is usually associated with the accumulation of newly deposited matrix, terminal differentiation of myofibroblasts and recruitment of immune cells that contribute to the fibrotic phenotype[7]. TGF-βactivates transcriptional regulators, such as β-catenin and Smads, and MAPK signalling to control the activity of key transcription factors during myofibroblast differentiation, inducing the expression of αSMA and other fibrotic marker genes such as collagens and fibronectin[8,9]. Our aim was to identify small molecules and molecular pathways that control terminal EMT stages linked to myofibroblast differentiation by using prolonged exposure of epithelial cells to TGF-β,followed by treatment with compounds from a chemical library. By studying further the crosstalk between TGF-βand LXR in the context of myofibroblast differentiation, we have uncovered a novel mechanism via which LXRαcan counteract the pro-fibrotic action of TGF-β
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