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

被引：7

作者：

Carthy, Jon M. ^{[1
,6
]}

Stoeter, Martin ^{[2
]}

Bellomo, Claudia ^{[1
,3
]}

Vanlandewijck, Michael ^{[1
,7
]}

Heldin, Angelos ^{[1
]}

Moren, Anita ^{[1
]}

Kardassis, Dimitris ^{[4
]}

Gahman, Timothy C. ^{[5
]}

Shiau, Andrew K. ^{[5
]}

Bickle, Marc ^{[2
]}

Zerial, Marino ^{[2
]}

Heldin, Carl-Henrik ^{[1
]}

Moustakas, Aristidis ^{[1
,3
]}

机构：

[1] Uppsala Univ, Sci Life Lab, Ludwig Inst Canc Res, Biomed Ctr, Box 595, SE-75124 Uppsala, Sweden

[2] Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany

[3] Uppsala Univ, Sci Life Lab, Dept Med Biochem & Microbiol, Biomed Ctr, Box 582, SE-75123 Uppsala, Sweden

[4] Univ Crete, Sch Med, Dept Biochem, Iraklion 71003, Crete, Greece

[5] Ludwig Inst Canc Res, Small Mol Discovery Program, La Jolla, CA 92093 USA

[6] Imperial Coll London, Fac Med, Div Brain Sci, London, England

[7] Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

基金：

瑞典研究理事会;

关键词：

TGF-BETA; MESENCHYMAL TRANSITION; GROWTH; INHIBITOR; EMT; PHARMACOLOGY; METABOLISM; ACTIVATION; PROTECTS; FIBROSIS;

D O I：

10.1038/srep29868

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 beta (TGF-beta)-induced epithelial-mesenchymal transition. In addition to TGF-beta 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 alpha-smooth muscle actin expression, myofibroblast differentiation and function. Agonist-dependent LXR activity or LXR overexpression in the absence of ligand counteracted TGF-beta-mediated myofibroblast terminal differentiation and collagen contraction. The protective effect of LXR agonists against TGF-beta-induced pro-fibrotic activity raises the possibility that anti-lipidogenic therapy may be relevant in fibrotic disorders and advanced cancer.

引用

页数：17

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