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Epithelial-to-mesenchymal transition correlates with gefitinib resistance in NSCLC cells and the liver X receptor ligand GW3965 reverses gefitinib resistance through inhibition of vimentin

Authors Hu Y, Zang J, Qin X, Yan D, Cao H, Zhou L, Ni J, Yu S, Wu J, Feng JF

Received 15 October 2016

Accepted for publication 11 March 2017

Published 28 April 2017 Volume 2017:10 Pages 2341—2348

DOI https://doi.org/10.2147/OTT.S124757

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Xuqi Li

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Geoffrey Pietersz

Yong Hu,1,* Jialan Zang,2,* Xiaobing Qin,1 Dali Yan,1 Haixia Cao,1 Leilei Zhou,1 Jie Ni,1 Shaorong Yu,1 Jianzhong Wu,1 Ji-Feng Feng1

1Research Center for Clinical Oncology, Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, 2Department of Oncology, The First Hospital of Harbin City, Harbin, Heilongjiang, People’s Republic of China

*These authors contributed equally to this work

Abstract: The role of epithelial-to-mesenchymal transition in cancer drug resistance is increasingly acknowledged. We examined whether epithelial-to-mesenchymal transition affects gefitinib resistance in non-small cell lung cancer (NSCLC) cells. Cell viability was detected by CCK-8 assay, VIM expression levels were determined by quantitative real-time polymerase chain reaction. Western blot and immunocytochemistry were performed to determine the protein expression level of vimentin. We observed morphologic differences between gefitinib-sensitive and -insensitive cells. Compared with the sensitive parental cell line, HCC827, vimentin expression levels were increased in HCC827 cells with acquired gefitinib resistance. Vimentin expression was also markedly upregulated in cells with intrinsic gefitinib resistance, and upregulated vimentin expression was correlated with gefitinib sensitivity. Our previous study demonstrated that coadministration of gefitinib and GW3965 resulted in decreased cell proliferation and induced apoptosis. Therefore, we investigated the relationship among GW3965, vimentin, and gefitinib resistance in NSCLC cells by analysis of the expression of vimentin in cells treated with a combination of gefitinib and GW3965. Gefitinib treatment led to increased levels of intracellular vimentin, while combined treatment with gefitinib and GW3965 resulted in decreased vimentin expression levels through reduction of gefitinib drug resistance in NSCLC cells. Overall, these findings suggest that vimentin expression is associated with sensitivity to gefitinib, and our study highlights the potential usefulness of the drug, GW3965, for reversal of gefitinib resistance through inhibition of vimentin expression.

Keywords: gefitinib resistance, LXR, EMT, GW3965, vimentin

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