Abstract
During non-small cell lung cancer (NSCLC) progression, transforming growth factor (TGF)-β mediated epithelial-to-mesenchymal transition (EMT) is an important process leading to high mortality and poor prognosis. The EMT is a fundamental process for morphogenesis characterized by the transformation of cancer cells into invasive forms that can be transferred to other organs during human lung cancer progression. Gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, has shown anti-proliferative effects in EGFR-mutated NSCLC cells and an inhibitory effect on migration and invasion of NSCLC cells to other organs. In this study, we evaluated the combinatorial treatment effect of cilengitide, a cyclic RGD pentapeptide, on TGF-β1-induced EMT phenotype and invasion. Gefitinib suppressed the expression of TGF-β1-induced mesenchymal markers by inhibiting Smad and non-Smad signaling pathways. Cilengitide enhanced the inhibitory effect of gefitinib on TGF-β1-induced expression of mesenchymal markers, phosphorylation of Smad2/3, and invasion of NSCLC A549 cells. We suggested that the use of cilengitide can improve the efficacy of anti-cancer drugs in combination drug-based chemotherapy. These results provide an improved therapeutic strategy for treating and preventing EMT-related disorders, such as NSCLC, lung fibrosis, cancer metastasis, and relapse.
Highlights
Among the various carcinomas, lung cancer is one of the major causes of cancer-related deaths worldwide and is increasing in incidence each year (Siegel et al, 2011)
Before evaluating the effect of gefitinib on the transforming growth factor (TGF)-β1-induced epithelial-to-mesenchymal transition (EMT), we investigated cell viability in non-small cell lung cancer (NSCLC) A549, normal lung fibroblast IMR90 and normal epithelial cell CPAE cells
The decreased expression of E-cadherin did not fully recover with gefitinib. This explains that gefitinib treatment cannot return cells that have already been transformed into mesenchymal cells by TGF-β1 to their original state, epithelial cell phenotype
Summary
Lung cancer is one of the major causes of cancer-related deaths worldwide and is increasing in incidence each year (Siegel et al, 2011). Among the various factors in cancers, transforming growth factor (TGF)-β is a major cytokine that induces invasion and metastasis through an EMT (Behrens et al, 1989; Buck and Knabbe, 2006; Barcellos-Hoff and Akhurst, 2009; Drabsch and ten Dijke, 2012). EMT-induced mobility and invasive potential play important roles in cancer metastasis to other organs. The metastatic process in lung cancer is a major cause of mortality and poor inhibition of signaling pathways associated with the EMT process is emerging as a new cancer treatment strategy
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