Novel inhibitor of TGF-β1 antagonizes TGF-β1-induced epithelial-to-mesenchymal transition in human A549 lung cancer cells

Abstract

Transforming growth factor β1(TGF-β1), a multifunctional cytokine, is known to promote tumor invasion, metastasis and induce epithelial-mesenchymal transition (EMT) in a variety of cancer cells. Inhibition of TGFβ signaling is a new strategy for cancer therapy. As the most cancer cells display altered or non-functional TGFβ signaling, TGFβ inhibitors have limited effects on these cells and exert their anti-tumoral activity by affecting TGF-β responsive cells. Recent study has revealed that down-regulation of cathepsin L suppresses cancer migration and invasion by inhibiting TGF-β1-mediated EMT in human A549 lung cancer cells. The aim of this study is to develop anti-TGF-β1 therapy for cancer. As suggested in recent reports, the development of a TGF-β1 inhibitor from natural compound is a key step in the development of a novel therapeutic agent. We found an improved analogue of chalcones, namely cathepsin B and L inhibitor, and investigated its anti-TGF-β1 effects in vitro. In this study, we investigated that the effects of chalcones, cathepsin B and L inhibitor on migration, invasion and EMT of human A549 lung cancer cells induced by TGF-β1. We demonstrated that chalcones blocked Smad-dependent TGF-β signaling pathway by inhibiting TGF-β1-induced Smad2 phosphorylation. Also, we observed that chalcones inhibit TGF-β1-mediated EMT. In conclusion, development of TGF-β inhibitor was helpful for therapy of tumor growth and metastasis. As a result, our research has found new inhibitors of TGF-β1 through the inhibition of Smad activity and EMT in human lung cancer cells. TGF-β inhibitor in cancer therapy is promising and opens new challenges in clinical trial.