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BIX02189 inhibits TGF-β1-induced lung cancer cell metastasis by directly targeting TGF-β type I receptor.
- Source :
-
Cancer Letters . Oct2016, Vol. 381 Issue 2, p314-322. 9p. - Publication Year :
- 2016
-
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]
- Subjects :
- *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
Subjects
Details
- Language :
- English
- ISSN :
- 03043835
- Volume :
- 381
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Cancer Letters
- Publication Type :
- Academic Journal
- Accession number :
- 118211364
- Full Text :
- https://doi.org/10.1016/j.canlet.2016.08.010