BIX02189 inhibits TGF-beta 1-induced lung cancer cell metastasis by directly targeting TGF-beta type I receptor

Abstract

Transforming growth factor-beta 1 (TGF-beta 1) 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-beta 1. In human A549 lung cancer cells, TGF-beta 1-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-beta 1 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-beta receptor type I (T beta RI) and suppresses its kinase activity. Finally, the anti-metastatic effect of BIX02189 was validated in a T beta RI-derived A549 xenograft mouse model. Collectively, these findings newly characterize BIX02189 as a potent inhibitor of T beta RI that can block the tumor metastatic activity of TGF-beta 1. (C) 2016 Elsevier Ireland Ltd. All rights reserved.