Suppression of epithelial mesenchymal transition by a novel Traf2- and Nck-interacting kinase inhibitory compound

Recently, we found that a novel Traf2- and Nck-interacting kinase (TNIK) inhibitor, named NCB-0846, was capable of attenuating tumor-initiating cells among human colorectal cancer. The cross link between EMT and cancer stemness has been revealed in several studies and other group showed another TNIK inhibitor named KY-05009 had inhibited the TGF-β-induced EMT. Therefore we evaluated whether this small-molecule compound could have efficacy to inhibit TGF-β-induced EMT. NCB-0846 reduced the expression of mesenchymal markers (Vimentin and N-cadherin) and upregulated the expression of epithelial marker E-cadherin in A549 and H2228 non-small cell lung cancer cells. NCB-0846 suppressed the phosphorylation and nuclear translocation of Smad proteins and also inhibited migration, invasion, and metastasis. NCB-0846 inhibited TGF-β1-induced EMT through the down-regulation of TGF-β receptor-1 (TβRI) in mRNA levels. MiR-186-5p and miR-320 family were identified as candidate miRNAs that could target TβRI and we found that miR-186-5p and miR-320s inhibited TβRI expression. NCB-0846 might be a novel therapeutics drugs that targets the invasion and metastasis through inhibiting TGF-β-induced EMT in lung cancer. EMT related markers and ability of migration, invasion, and metastasis were examined after exposure to TGF-B1 only or co-treated with TGF-B1 and NCB-0846 or NCB-970.