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Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846

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-...

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Autores principales: Sugano, Teppei, Masuda, Mari, Takeshita, Fumitaka, Motoi, Noriko, Hirozane, Toru, Goto, Naoko, Kashimoto, Shigeki, Uno, Yuko, Moriyama, Hideki, Sawa, Masaaki, Nagakawa, Yuichi, Tsuchida, Akihiko, Seike, Masahiro, Gemma, Akihiko, Yamada, Tesshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782820/
https://www.ncbi.nlm.nih.gov/pubmed/33244122
http://dx.doi.org/10.1038/s41416-020-01162-3
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author Sugano, Teppei
Masuda, Mari
Takeshita, Fumitaka
Motoi, Noriko
Hirozane, Toru
Goto, Naoko
Kashimoto, Shigeki
Uno, Yuko
Moriyama, Hideki
Sawa, Masaaki
Nagakawa, Yuichi
Tsuchida, Akihiko
Seike, Masahiro
Gemma, Akihiko
Yamada, Tesshi
author_facet Sugano, Teppei
Masuda, Mari
Takeshita, Fumitaka
Motoi, Noriko
Hirozane, Toru
Goto, Naoko
Kashimoto, Shigeki
Uno, Yuko
Moriyama, Hideki
Sawa, Masaaki
Nagakawa, Yuichi
Tsuchida, Akihiko
Seike, Masahiro
Gemma, Akihiko
Yamada, Tesshi
author_sort Sugano, Teppei
collection PubMed
description 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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spelling pubmed-77828202021-11-27 Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846 Sugano, Teppei Masuda, Mari Takeshita, Fumitaka Motoi, Noriko Hirozane, Toru Goto, Naoko Kashimoto, Shigeki Uno, Yuko Moriyama, Hideki Sawa, Masaaki Nagakawa, Yuichi Tsuchida, Akihiko Seike, Masahiro Gemma, Akihiko Yamada, Tesshi Br J Cancer Article 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. Nature Publishing Group UK 2020-11-27 2021-01-05 /pmc/articles/PMC7782820/ /pubmed/33244122 http://dx.doi.org/10.1038/s41416-020-01162-3 Text en © The Author(s), under exclusive licence to Cancer Research UK 2020 https://creativecommons.org/licenses/by/4.0/ Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).
spellingShingle Article
Sugano, Teppei
Masuda, Mari
Takeshita, Fumitaka
Motoi, Noriko
Hirozane, Toru
Goto, Naoko
Kashimoto, Shigeki
Uno, Yuko
Moriyama, Hideki
Sawa, Masaaki
Nagakawa, Yuichi
Tsuchida, Akihiko
Seike, Masahiro
Gemma, Akihiko
Yamada, Tesshi
Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846
title Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846
title_full Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846
title_fullStr Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846
title_full_unstemmed Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846
title_short Pharmacological blockage of transforming growth factor-β signalling by a Traf2- and Nck-interacting kinase inhibitor, NCB-0846
title_sort pharmacological blockage of transforming growth factor-β signalling by a traf2- and nck-interacting kinase inhibitor, ncb-0846
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782820/
https://www.ncbi.nlm.nih.gov/pubmed/33244122
http://dx.doi.org/10.1038/s41416-020-01162-3
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