TNIK inhibition abrogates colorectal cancer stemness.
Mari MasudaYuko UnoNaomi OhbayashiHirokazu OhataAyako MimataMutsuko Kukimoto-NiinoHideki MoriyamaShigeki KashimotoTomoko InoueNaoko GotoKoji OkamotoMikako ShirouzuMasaaki SawaTesshi YamadaPublished in: Nature communications (2016)
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(-/-)/Apc(min/+) 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 Apc(min/+) 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.
Keyphrases
- stem cells
- cell proliferation
- crystal structure
- small molecule
- cancer stem cells
- epithelial mesenchymal transition
- signaling pathway
- transcription factor
- high fat diet induced
- gene expression
- tyrosine kinase
- magnetic resonance imaging
- oxidative stress
- wild type
- bone marrow
- adipose tissue
- magnetic resonance
- metabolic syndrome
- endothelial cells
- insulin resistance
- binding protein