BIX02189 inhibits TGF-ß1-induced lung cancer cell metastasis by directly targeting TGF-ß type I receptor.
Cancer Lett
; 381(2): 314-22, 2016 10 28.
Article
em En
| MEDLINE
| ID: mdl-27543359
ABSTRACT
Transforming growth factor-ß1 (TGF-ß1) 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-ß1. In human A549 lung cancer cells, TGF-ß1-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-ß1 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-ß receptor type I (TßRI) and suppresses its kinase activity. Finally, the anti-metastatic effect of BIX02189 was validated in a TßRI-derived A549 xenograft mouse model. Collectively, these findings newly characterize BIX02189 as a potent inhibitor of TßRI that can block the tumor metastatic activity of TGF-ß1.
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MEDLINE
Assunto principal:
Movimento Celular
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Proteínas Serina-Treonina Quinases
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Receptores de Fatores de Crescimento Transformadores beta
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Carcinoma Pulmonar de Células não Pequenas
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Inibidores de Proteínas Quinases
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Fator de Crescimento Transformador beta1
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Indóis
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Compostos de Anilina
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Neoplasias Pulmonares
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Cancer Lett
Ano de publicação:
2016
Tipo de documento:
Article