Abstract
Lung carcinogenesis is a complex process that occurs in unregulated inflammatory environment. EGCG has been extensively investigated as a multi-targeting anti-tumor and anti-inflammatory compound. In this study, we demonstrated a novel mechanism by which EGCG reverses the neutrophil elastase-induced migration of A549 cells. We found that neutrophil elastase directly triggered human adenocarcinoma A549 cell migration and that EGCG suppressed the elevation of tumor cell migration induced by neutrophil elastase. We observed that EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity based on the CDOCKER algorithm, MD stimulation by GROMACS, SPR assay and elastase enzymatic activity assay. As the natural inhibitor of neutrophil elastase, α1-antitrypsin is synthesized in tumor cells. We further demonstrated that the expression of α1-antitrypsin was up-regulated after EGCG treatment in neutrophil elastase-treated A549 cells. We preliminarily discovered that the EGCG-mediated induction of α1-antitrypsin expression might be correlated with the regulatory effect of EGCG on the PI3K/Akt pathway. Overall, our results suggest that EGCG ameliorates the neutrophil elastase-induced migration of A549 cells. The mechanism underlying this effect may include two processes: EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity; EGCG enhances the expression of α1-antitrypsin by regulating the PI3K/AKT pathway.
Highlights
Signaling pathways, such as the activator protein (AP), nuclear factor-κ B (NF-κ B), and phosphatidylinostitol–3-OH kinase pathways (PI3K/Akt)[5,6,7]
EGCG inhibits tumor cell migration induced by neutrophil elastase but does not influence the proliferation of A549 cells
The MTS proliferation assay results showed similar cell viability between the control group and the groups treated with various concentrations of EGCG (Fig. 1C) and showed a non-significant change in cell viability between the group treated with neutrophil elastase (10 nM) and the groups treated with EGCG and neutrophil elastase (10 nM)
Summary
Signaling pathways, such as the activator protein (AP), nuclear factor-κ B (NF-κ B), and phosphatidylinostitol–3-OH kinase pathways (PI3K/Akt)[5,6,7]. We demonstrated additional contributions of inflammation to the progression of lung cancer metastasis and a novel molecular target of EGCG, human neutrophil elastase, which induces lung cancer cell migration. Neutrophils, as a component of the tumor microenvironment, have only recently been thought to play an important role in tumor growth and invasiveness[9]. As an acute-phase protein, AAT is thought to play an important role in limiting host tissue injury triggered by proteases, human neutrophil elastase (HNE). It has been assumed that in AAT-deficiency, the protease/ anti-protease balance is shifted toward HNE, which leads to extensive tissue damage, by causing emphysema. Xu et al.[14] demonstrated that the natural polyphenol product curcumin inhibits tumor proliferation induced by neutrophil elastase via the upregulation of AAT in lung cancer. Altering the balance between AAT and HNE may represent an innovative form of lung cancer treatment
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