BIX02189 inhibits TGF-β1-induced lung cancer cell metastasis by directly targeting TGF-β type I receptor. Issue 2 (28th October 2016)

• Record Type: Journal Article
• Authors: Park, Seong Ji; Choi, Yu Sun; Lee, Seungkoo; Lee, Young Jae; Hong, Suntaek; Han, Sanghwa; Kim, Byung-Chul
• Is Part Of: Cancer letters. Volume 381:Issue 2(2016)
• Page Start: 314
• Page End: 322
• Publication Date: 2016-10-28
• Subjects: BLI bioluminescent imaging -- EGF epidermal growth factor -- EMT epithelial-to-mesenchymal transition -- ERK extracellular-signal-regulated kinase -- Fluc firefly luciferase -- MAPK mitogen-activated protein kinase -- MEK5 mitogen-activated protein kinase/extracellular-signal-regulated kinase5 -- MMP matrix metalloproteinase -- PBS phosphate buffered saline -- siRNA small interfering RNA -- TβRI transforming growth factor-β1 receptor type I -- TGF-β1 transforming growth factor-β1; BIX02189 -- TβRI -- TGF-β1 -- EMT -- Lung cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.08.010
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: BIX02189 inhibits TGF-β1-induced EMT and cell migration in A549 lung cancer cells. The inhibitory effect of BIX02189 is independent of its action as a MEK5 inhibitor. BIX02189 directly binds to TβRI and suppresses its kinase activity. BIX02189 blocks the metastatic spread of A549 cells in a xenograft mouse model. BIX02189 may have use as a potential therapeutic agent for human lung cancer. Abstract: Transforming growth factor-β1 (TGF-β1) promotes tumor metastasis by inducing an epithelial-to-mesenchymal transition (EMT) in cancer cells. In this study, we investigated the effects of BIX02189 and XMD8-92, pharmacologic inhibitors of the MEK5 [mitogen-activated protein kinase/extracellular-signal-regulated kinase (ERK)5] signaling pathway, on the EMT and migration of cancer cells induced by TGF-β1. In human A549 lung cancer cells, TGF-β1-induced EMT, cell motility, and expression of matrix metalloproteinase-2 were completely inhibited by BIX02189, but not by XMD8-92 or small interference RNAs specific to MEK5 and ERK5. Interestingly, BIX02189 strongly blocked the activation of TGF-β1 signaling components, and this inhibitory effect was not reproduced by MEK5 inhibition. Molecular docking simulation and kinase assays revealed that BIX02189 binds directly to the ATP-binding site of the TGF-β receptor type I (TβRI) and suppresses its kinase activity. Finally, the anti-metastatic effect of BIX02189 was validated in a TβRI-derived A549 xenograft mouse model. Collectively, these findings newly characterize BIX02189 as a potent inhibitor of TβRI that can block the tumor metastatic activity of TGF-β1.