Pentabromophenol suppresses TGF-β signaling by accelerating degradation of type II TGF-β receptors via caveolae-mediated endocytosis

Pentabromophenol (PBP), a brominated flame retardant (BFR), is widely used in various consumer products. BFRs exert adverse health effects such as neurotoxic and endocrine-disrupting effects. In this study, we found that PBP suppressed TGF-beta response by accelerating the turnover rate of TGF-beta receptors. PBP suppressed TGF-beta-mediated cell migration, PAI-1 promoter-driven reporter gene activation, and Smad2/3 phosphorylation in various cell types. Furthermore, PBP abolished TGF-beta mediated repression of E-cadherin expression, in addition to the induction of vimentin expression and N-cadherin and fibronectin upregulation, thus blocking TGF-beta-induced epithelial-mesenchymal transition in A549 and NMuMG cells. However, this inhibition was not observed with other congeners such as tribromophenol and triiodophenol. TGF-beta superfamily members play key roles in regulating various biological processes including cell proliferation and migration as well as cancer development and progression. The results of this in vitro study provide a basis for studies on the detailed relationship between PBP and modulation of TGF-beta signalling. Because PBP is similar to other BFRs such as polybrominated diphenyl ethers (PBDEs), additional laboratory and mechanistic studies should be performed to examine BFRs as potential risk factors for tumorigenesis and other TGF-beta-related diseases.