Pentachloropseudilin Inhibits Transforming Growth Factor-ß (TGF-ß) Activity by Accelerating Cell-Surface Type†II TGF-ß Receptor Turnover in Target Cells.

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-ß (TGF-ß)-stimulated signaling. PCIP inhibits TGF-ß-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-ß-stimulated expression of vimentin, N-cadherin, and fibronectin and, thus, blocks TGF-ß-induced epithelial to mesenchymal transition (EMT) in these cells. Furthermore, cell-surface labeling and immunoblot analysis indicates that PCIP suppresses TGF-ß-stimulated cellular responses by attenuating cell-surface expression of the type II TGF-ß 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.