title: Overexpression of PAD4 suppresses drug resistance of NSCLC cell lines to gefitinib through inhibiting Elk1-mediated epithelial-mesenchymal transition.
abstract: It is reported that epithelial-to-mesenchymal transition (EMT) could induce resistance in tumor cells, and knockdown of peptidylarginine deiminase IV (PAD4) induces the activity of EMT. However, the role of PAD4 in gefitinib‑acquired resistance in non-small cell lung cancer (NSCLC) remains unclear. In this study, we aimed to investigate the role of PAD4 in the resistance of NSCLC to gefitinib. The cells resistant to gefitinib were established in accordance with the literature, and were derived from NSCLC cell lines HCC827 and H1650. Real-time quantitative PCR and western blot results showed that PAD4 was obviously downregulated in the cells resistant to gefitinib. Overexpression of PAD4 distinctly inhibited gefitinib resistance, whereas PAD4 downregulation had the opposite effect. Further data indicated that PAD4 upregulation could restrain EMT activity via controlling the expression of ETS-domain containing protein (Elk1). Conversely, inhibition of PAD4 showed the reverse function compared with PAD4 upregulation. Above all, our study showed that overexpression of PAD4 constrains the activity of EMT via suppressing Elk1 expression, and inhibits resistance of NSCLC to gefitinib.
authors.affiliation: Department of Oncology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Duan
authors.affiliation: Department of Oncology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Cui
authors.initials: C
authors.lastname: Pang
authors.affiliation: Department of Respiratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Ning
authors.initials: N
authors.lastname: Chang
authors.affiliation: Institute of Gene Diagnosis, State Key Laboratory of Cancer Biology, School of Pharmacology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Ju
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Liu
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D050807:ets-Domain Protein Elk-1 / Q000235:genetics
chemical_list: C494112:ELK1 protein, human; D011799:Quinazolines; D050807:ets-Domain Protein Elk-1; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D000077156:Gefitinib