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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-...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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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. |
format | Online Article Text |
id | pubmed-7782820 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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