1. BIX02189 inhibits TGF-β1-induced lung cancer cell metastasis by directly targeting TGF-β type I receptor.
- Author
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Park, Seong Ji, Choi, Yu Sun, Lee, Seungkoo, Lee, Young Jae, Hong, Suntaek, Han, Sanghwa, and Kim, Byung-Chul
- Subjects
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TRANSFORMING growth factors , *LUNG cancer , *CANCER cells , *METASTASIS , *CELLULAR signal transduction , *ADENOSINE triphosphate metabolism , *AMINES , *ANIMAL experimentation , *ANIMALS , *ANTINEOPLASTIC agents , *BINDING sites , *CANCER invasiveness , *CARRIER proteins , *CELL receptors , *CELL motility , *COMPUTER simulation , *DOSE-effect relationship in pharmacology , *GENES , *GENETIC techniques , *GROWTH factors , *LUNG tumors , *MICE , *TRANSFERASES , *INDOLE compounds , *PROTEIN kinase inhibitors , *PHARMACODYNAMICS - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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