Inhibition of ZEB1 reverses EMT and chemoresistance in docetaxel-resistant human lung adenocarcinoma cell line

Abstract

Docetaxel has been used as one of the first-line chemotherapies in solid tumors including advanced non-small cell lung cancer (NSCLC). However, limited responses to chemotherapy are observed in clinic and the molecular mechanisms have not been fully understood. Emerging evidence suggests that epithelial-mesenchymal transition (EMT) plays an important role in the processes of tumor metastasis as well as resistance towards anticancer agents. In this study, it was observed that docetaxel-resistant human lung adenocarcinoma cell line (SPC-A1/DTX) was typical of mesenchymal phenotype. SPC-A1/DTX cell line has increased migratory and invasive capacity both in vitro and in vivo. Among the master EMT-inducing transcriptional factors, ZEB1 was found to be significantly increased in SPC-A1/DTX cell line. ZEB1 knockdown with RNA interference could reverse the EMT phenotype and inhibit the migratory ability of SPC-A1/DTX cells. Furthermore, inhibition of ZEB1 significantly enhanced the chemosensitivity of SPC-A1/DTX cells to docetaxel in vitro and in vivo and ectopic expression of ZEB1 increased the chemoresistance of SPC-A1 cells to docetaxel. All these results provide experimental evidence that ZEB1 might be an attractive target for the treatment of human NSCLC.