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BIX02189 inhibits TGF-β1-induced lung cancer cell metastasis by directly targeting TGF-β type I receptor
Seong Ji Park1, Yu Sun Choi1, Seungkoo Lee2
1Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
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.
Insights
BIX02189 effectively inhibits transforming growth factor-β1 (TGF-β1)-induced tumor metastasis by targeting the TGF-β receptor type I (TβRI). This compound blocks cancer cell epithelial-to-mesenchymal transition (EMT) and migration, offering a potential anti-metastatic therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Transforming growth factor-β1 (TGF-β1) is a key driver of tumor metastasis through epithelial-to-mesenchymal transition (EMT).
- Targeting the TGF-β1 signaling pathway is a promising strategy for anti-cancer therapies.
- MEK5/ERK5 pathway inhibitors were investigated for their effects on TGF-β1-induced EMT.
Purpose of the Study:
- To investigate the efficacy of BIX02189 and XMD8-92, MEK5/ERK5 pathway inhibitors, against TGF-β1-induced EMT and cancer cell migration.
- To elucidate the molecular mechanism underlying the action of BIX02189.
- To validate the anti-metastatic potential of BIX02189 in vivo.
Main Methods:
- In vitro studies using A549 lung cancer cells treated with TGF-β1, BIX02189, XMD8-92, and siRNAs.
- Analysis of EMT markers, cell motility, and matrix metalloproteinase-2 expression.
- Molecular docking simulations and kinase assays.
- In vivo validation using a TβRI-derived A549 xenograft mouse model.
Main Results:
- BIX02189 completely inhibited TGF-β1-induced EMT, cell motility, and matrix metalloproteinase-2 expression in A549 cells.
- XMD8-92 and MEK5/ERK5 siRNAs did not replicate the inhibitory effects of BIX02189.
- BIX02189 directly binds to and inhibits the kinase activity of TGF-β receptor type I (TβRI).
- BIX02189 demonstrated anti-metastatic effects in a xenograft mouse model.
Conclusions:
- BIX02189 is a potent inhibitor of TβRI kinase activity, distinct from its effects on the MEK5/ERK5 pathway.
- BIX02189 effectively blocks TGF-β1-induced tumor cell metastasis.
- BIX02189 represents a promising therapeutic candidate for inhibiting cancer metastasis.
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