a Department of Biological Sciences , National Sun Yat-sen University , Kaohsiung , Taiwan, ROC.
b Department of Chemistry , TU Dresden , Dresden , Germany.
J Enzyme Inhib Med Chem. 2018 Dec;33(1):920-935. doi: 10.1080/14756366.2018.1465416.
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.
五溴基 Pseudilin（PBrP）是一种从海洋细菌假单胞菌溴和交替单胞菌属分离出来的海洋抗生素。PBrP 具有抗菌、抗肿瘤和植物毒性活性。在哺乳动物细胞中，PBrP 被认为是肌球蛋白 Va（MyoVa）的可逆变构抑制剂。在这项研究中，我们报告 PBrP 是转化生长因子-β（TGF-β）活性的有效抑制剂。PBrP 抑制 TGF-β 刺激的 Smad2/3 磷酸化、纤溶酶原激活物抑制剂-1（PAI-1）蛋白的产生，并阻断 TGF-β诱导的上皮细胞间充质转化。PBrP 通过降低细胞表面 II 型 TGF-β受体（TβRII）的表达并促进受体降解来抑制 TGF-β信号转导。基因沉默方法表明，MyoVa 在 PBrP 诱导的 TβRII 周转和随后的 TGF-β信号转导减少中发挥关键作用。由于 TGF-β信号转导在组织纤维化和癌症发展等多种病理生理过程的调节中至关重要，因此应该进一步探索 PBrP 在治疗纤维化疾病和癌症方面的治疗作用。
