Pentabromopseudilin: a myosin V inhibitor suppresses TGF-β activity by recruiting the type II TGF-β receptor to lysosomal degradation

J Enzyme Inhib Med Chem. 2018 Dec;33(1):920-935. doi: 10.1080/14756366.2018.1465416.

Abstract

Pentabromopseudilin (PBrP) is a marine antibiotic isolated from the marine bacteria Pseudomonas bromoutilis and Alteromonas luteoviolaceus. PBrP exhibits antimicrobial, anti-tumour, and phytotoxic activities. In mammalian cells, PBrP is known to act as a reversible and allosteric inhibitor of myosin Va (MyoVa). In this study, we report that PBrP is a potent inhibitor of transforming growth factor-β (TGF-β) activity. PBrP inhibits TGF-β-stimulated Smad2/3 phosphorylation, plasminogen activator inhibitor-1 (PAI-1) protein production and blocks TGF-β-induced epithelial-mesenchymal transition in epithelial cells. PBrP inhibits TGF-β signalling by reducing the cell-surface expression of type II TGF-β receptor (TβRII) and promotes receptor degradation. Gene silencing approaches suggest that MyoVa plays a crucial role in PBrP-induced TβRII turnover and the subsequent reduction of TGF-β signalling. Because, TGF-β signalling is crucial in the regulation of diverse pathophysiological processes such as tissue fibrosis and cancer development, PBrP should be further explored for its therapeutic role in treating fibrotic diseases and cancer.

Keywords: Myosin V; TGF-β; lipid-raft; pentabromopseudilin; subcellular trafficking.

MeSH terms

  • Alteromonas / chemistry
  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Lysosomes / drug effects*
  • Lysosomes / metabolism*
  • Mink
  • Molecular Structure
  • Myosin Type V / antagonists & inhibitors*
  • Myosin Type V / metabolism
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / biosynthesis
  • Pseudomonas / chemistry
  • Pyrroles / chemistry
  • Pyrroles / isolation & purification
  • Pyrroles / pharmacology*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Receptors, Transforming Growth Factor beta / biosynthesis
  • Structure-Activity Relationship
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta / metabolism

Substances

  • Pyrroles
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • pentabromopseudilin
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Myosin Type V

Grants and funding

This study was supported by the Ministry of Science and Technology of Taiwan (101–2320-B-110–003, 102–2320-B-110–007 and 105–2628-B-110–003-MY3), KMU Stem Cell Center (KMU-TP105G00, KMU-TP105G0 and KMU-TP105G02) and NSYSU-KMU Joint Research Project (NSYSUKMU 106-I009 and 107-I001).