A novel aminothiazole KY-05009 with potential to inhibit Traf2- and Nck-interacting kinase (TNIK) attenuates TGF-β1-mediated epithelial-to-mesenchymal transition in human lung adenocarcinoma A549 cells.

Jiyeon Kim,Chong Hak Chae,Seong-Hee Moon,Seong Hwan Kim,Joo Yun Lee,Bum Tae Kim,Neil A Hotchin

doi:10.1371/journal.pone.0110180

Jiyeon Kim, Chong Hak Chae + Show 5 more

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https://doi.org/10.1371/journal.pone.0110180

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Abstract

Transforming growth factor (TGF)-β triggers the epithelial-to-mesenchymal transition (EMT) of cancer cells via well-orchestrated crosstalk between Smad and non-Smad signaling pathways, including Wnt/β-catenin. Since EMT-induced motility and invasion play a critical role in cancer metastasis, EMT-related molecules are emerging as novel targets of anti-cancer therapies. Traf2- and Nck-interacting kinase (TNIK) has recently been considered as a first-in-class anti-cancer target molecule to regulate Wnt signaling pathway, but pharmacologic inhibition of its EMT activity has not yet been studied. Here, using 5-(4-methylbenzamido)-2-(phenylamino)thiazole-4-carboxamide (KY-05009) with TNIK-inhibitory activity, its efficacy to inhibit EMT in cancer cells was validated. The molecular docking/binding study revealed the binding of KY-05009 in the hinge region of TNIK, and the inhibitory activity of KY-05009 against TNIK was confirmed by an ATP competition assay (K i, 100 nM). In A549 cells, KY-05009 significantly and strongly inhibited the TGF-β-activated EMT through the attenuation of Smad and non-Smad signaling pathways, including the Wnt, NF-κB, FAK-Src-paxillin-related focal adhesion, and MAP kinases (ERK and JNK) signaling pathways. Continuing efforts to identify and validate potential therapeutic targets associated with EMT, such as TNIK, provide new and improved therapies for treating and/or preventing EMT-based disorders, such as cancer metastasis and fibrosis.

Highlights

Epithelial-to-mesenchymal transition (EMT) is the complicated process of change that epithelial cells undergo to acquire the characteristics of mesenchymal cells during embryogenesis, development, wound healing, organ fibrosis, and cancer metastasis [1,2]
Before evaluating the effect of KY-05009 on Transforming growth factor (TGF)-b-mediated EMT in human lung adenocarcinoma A549 cells, we investigated the binding mode and main interactions of KY-05009 with Traf2- and Nck-interacting kinase (TNIK)
To address this relevance, we performed this study to investigate the effects of KY-05009 with the potential to inhibit TNIK activity, on TGF-b-induced EMT in A549 cells

Summary

Introduction

Epithelial-to-mesenchymal transition (EMT) is the complicated process of change that epithelial cells undergo to acquire the characteristics of mesenchymal cells during embryogenesis, development, wound healing, organ fibrosis, and cancer metastasis [1,2]. As they undergo EMT, the polarized and closely packed epithelial cells become more motile and invasive, which are the main characteristics of spindle-shaped mesenchymal cells. Transforming growth factor (TGF)-b is the major cytokine that triggers EMT during cancer progression and metastasis [3,4,5,6]. The phosphorylated Smad2/3 complex recruits Smad, this trimeric complex further translocates into the nucleus, where it binds to transcription factors, such as Snail/Slug and Twist, to activate TGF-bresponsive genes [7,8,9,10,11,12]

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