TNIK inhibition abrogates colorectal cancer stemness
| العنوان: | TNIK inhibition abrogates colorectal cancer stemness |
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| المؤلفون: | Tesshi Yamada, Naomi Ohbayashi, Hideki Moriyama, Mari Masuda, Ayako Mimata, Yuko Uno, Koji Okamoto, Mutsuko Kukimoto-Niino, Hirokazu Ohata, Shigeki Kashimoto, Mikako Shirouzu, Tomoko Inoue, Masaaki Sawa, Naoko Goto |
| المصدر: | Nature Communications Nature Communications, Vol 7, Iss 1, Pp 1-14 (2016) |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Colorectal cancer, Carcinogenesis, General Physics and Astronomy, Administration, Oral, medicine.disease_cause, Crystallography, X-Ray, Germinal Center Kinases, Mice, Wnt Signaling Pathway, beta Catenin, Mice, Knockout, Mice, Inbred BALB C, Multidisciplinary, biology, Kinase, Wnt signaling pathway, Imidazoles, Middle Aged, Recombinant Proteins, Cell Transformation, Neoplastic, Neoplastic Stem Cells, Female, Stem cell, Colorectal Neoplasms, Protein Binding, Beta-catenin, Science, Ubiquitin-Protein Ligases, Adenomatous Polyposis Coli Protein, Azoxymethane, Mice, Nude, Protein Serine-Threonine Kinases, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Protein Kinase Inhibitors, Aged, Cell Proliferation, Cell growth, General Chemistry, medicine.disease, Xenograft Model Antitumor Assays, Mice, Inbred C57BL, Wnt Proteins, 030104 developmental biology, TNIK, Mutation, biology.protein, Cancer research, Quinazolines |
| الوصف: | Canonical Wnt/β-catenin signalling is essential for maintaining intestinal stem cells, and its constitutive activation has been implicated in colorectal carcinogenesis. We and others have previously identified Traf2- and Nck-interacting kinase (TNIK) as an essential regulatory component of the T-cell factor-4 and β-catenin transcriptional complex. Consistent with this, Tnik-deficient mice are resistant to azoxymethane-induced colon tumorigenesis, and Tnik−/−/Apcmin/+ mutant mice develop significantly fewer intestinal tumours. Here we report the first orally available small-molecule TNIK inhibitor, NCB-0846, having anti-Wnt activity. X-ray co-crystal structure analysis reveals that NCB-0846 binds to TNIK in an inactive conformation, and this binding mode seems to be essential for Wnt inhibition. NCB-0846 suppresses Wnt-driven intestinal tumorigenesis in Apcmin/+ mice and the sphere- and tumour-forming activities of colorectal cancer cells. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach. TRAF2 and NCK-interacting protein kinase (TNIK) is a key regulatory component of the TCF4 and β-catenin transcriptional complex. In this study, the authors identify a TNIK inhibitor that blocks Wnt signalling and Wnt-driven colorectal tumorigenesis in mice. |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d47f6706e9c39ac4521f3bb3d6f0a69d https://pubmed.ncbi.nlm.nih.gov/27562646 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....d47f6706e9c39ac4521f3bb3d6f0a69d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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