期刊
CHEMBIOCHEM
卷 19, 期 8, 页码 851-864出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201700693
关键词
growth factors; inhibitors; lipid rafts; organohalogen metabolites; receptor trafficking
资金
- Ministry of Science and Technology of Taiwan [101-2320-B-110-003, 102-2320-B-110-007, 105-2628-B-110-003-MY3]
- KMU Stem Cell Center [KMU-TP105G00, KMU-TP105G0, KMU-TP105G02]
- NSYSU-KMU Joint Research Project [NSYSUKMU 106-I009, 107-I001]
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 myosin1c (Myo1c). Herein, we report that PCIP is a potent inhibitor of transforming growth factor- (TGF-)-stimulated signaling. PCIP inhibits TGF--stimulated Smad2/3 phosphorylation and plasminogen activator inhibitor-1 (PAI-1) promoter activation with an IC50 of 0.1m in target cells (A549, HepG2, and Mv1Lu cells). In addition, PCIP attenuates TGF--stimulated expression of vimentin, N-cadherin, and fibronectin and, thus, blocks TGF--induced epithelial to mesenchymal transition (EMT) in these cells. Furthermore, cell-surface labeling and immunoblot analysis indicates that PCIP suppresses TGF--stimulated cellular responses by attenuating cell-surface expression of the typeII TGF- 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.
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