Pentachloropseudilin Inhibits Transforming Growth Factor‐β (TGF‐β) Activity by Accelerating Cell‐Surface Type II TGF‐β Receptor Turnover in Target Cells. (2nd March 2018)

• Record Type: Journal Article
• Authors: Chung, Chih‐Ling; Wang, Shih‐Wei; Martin, René; Knölker, Hans‐Joachim; Kao, Yu‐Chen; Lin, Ming‐Hong; Chen, Jih‐Jung; Huang, Yaw‐Bin; Wu, Deng‐Chyang; Chen, Chun‐Lin
• Is Part Of: Chembiochem. Volume 19:Number 8(2018)
• Page Start: 851
• Page End: 864
• Publication Date: 2018-03-02
• Subjects: growth factors -- inhibitors -- lipid rafts -- organohalogen metabolites -- receptor trafficking; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201700693
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: Pentachloropseudilin (PClP) is a chlorinated phenylpyrrole compound that was first isolated from Actinoplanes (ATCC33002), and its structure has been confirmed by chemical synthesis. PClP shows broad antimicrobial activity against Gram‐negative and Gram‐positive bacteria, protozoa, fungi, and yeast. In mammalian cells, PClP is known to act as a reversible and allosteric inhibitor of myosin 1c (Myo1c). Herein, we report that PCIP is a potent inhibitor of transforming growth factor‐β (TGF‐β)‐stimulated signaling. PCIP inhibits TGF‐β‐stimulated Smad2/3 phosphorylation and plasminogen activator inhibitor‐1 (PAI‐1) promoter activation with an IC50 of 0.1 μm in target cells (A549, HepG2, and Mv1Lu cells). In addition, PCIP attenuates TGF‐β‐stimulated expression of vimentin, N ‐cadherin, and fibronectin and, thus, blocks TGF‐β‐induced epithelial to mesenchymal transition (EMT) in these cells. Furthermore, cell‐surface labeling and immunoblot analysis indicates that PCIP suppresses TGF‐β‐stimulated cellular responses by attenuating cell‐surface expression of the type II TGF‐β receptor through accelerating caveolae‐mediated internalization followed by primarily lysosome‐dependent degradation of the receptor, as demonstrated by sucrose density gradient analysis and immune fluorescence staining. Abstract : Mixed signals : Pentachloropseudilin treatment results in the accumulation of type II TGF‐β receptor (TβR‐II) in the recycling perinuclear compartments, subsequent degradation of these cytoplasmic TGF‐β receptors in lysosomes, and thus decreased cell‐surface expression of TβR‐II and down‐regulation of TGF‐β‐stimulated signaling at the cell surface and its downstream responses.