Pharmacological blockage of transforming growth factor-β signalling by a Traf2-and Nck-interacting kinase inhibitor, NCB-0846
T Sugano, M Masuda, F Takeshita, N Motoi… - British Journal of …, 2021 - nature.com
T Sugano, M Masuda, F Takeshita, N Motoi, T Hirozane, N Goto, S Kashimoto, Y Uno…
British Journal of Cancer, 2021•nature.comBackground Metastasis is the primary cause of death in cancer patients, and its
management is still a major challenge. Epithelial to mesenchymal transition (EMT) has been
implicated in the process of cancer metastasis, and its pharmacological interference holds
therapeutic promise. Methods Traf2-and Nck-interacting kinase (TNIK) functions as a
transcriptional coregulator of Wnt target genes. Given the convergence of Wnt and
transforming growth factor-β (TGFβ) signalling, we examined the effects of a small-molecule …
management is still a major challenge. Epithelial to mesenchymal transition (EMT) has been
implicated in the process of cancer metastasis, and its pharmacological interference holds
therapeutic promise. Methods Traf2-and Nck-interacting kinase (TNIK) functions as a
transcriptional coregulator of Wnt target genes. Given the convergence of Wnt and
transforming growth factor-β (TGFβ) signalling, we examined the effects of a small-molecule …
Background
Metastasis is the primary cause of death in cancer patients, and its management is still a major challenge. Epithelial to mesenchymal transition (EMT) has been implicated in the process of cancer metastasis, and its pharmacological interference holds therapeutic promise.
Methods
Traf2- and Nck-interacting kinase (TNIK) functions as a transcriptional coregulator of Wnt target genes. Given the convergence of Wnt and transforming growth factor-β (TGFβ) signalling, we examined the effects of a small-molecule TNIK inhibitor (named NCB-0846) on the TGFβ1-induced EMT of lung cancer cells.
Results
NCB-0846 inhibited the TGFβ1-induced EMT of A549 cells. This inhibition was associated with inhibition of Sma- and Mad-Related Protein-2/3 (SMAD2/3) phosphorylation and nuclear translocation. NCB-0846 abolished the lung metastasis of TGFβ1-treated A549 cells injected into the tail veins of immunodeficient mice. The inhibition of EMT was mediated by suppression of the TGFβ receptor type-I (TGFBR1) gene, at least partly through the induction of microRNAs targeting the TGFBR1 transcript [miR-320 (a, b and d) and miR-186].
Conclusions
NCB-0846 pharmacologically blocks the TGFβ/SMAD signalling and EMT induction of lung cancer cells by transcriptionally downregulating TGFBRI expression, representing a potentially promising approach for prevention of metastasis in lung cancer patients.
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