title: DDX17 nucleocytoplasmic shuttling promotes acquired gefitinib resistance in non-small cell lung cancer cells via activation of β-catenin.
abstract: Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective for non-small cell lung cancer (NSCLC) patients with EGFR mutations, almost all these patients will eventually develop acquired resistance to EGFR-TKI. However, the molecular mechanisms responsible for gefitinib resistance remain still not fully understood. Here, we report that elevated DDX17 levels are observed in gefitinib-resistant NSCLC cells than gefitinib-sensitive cells. Upregulation of DDX17 enhances the gefitinib resistance, whereas DDX17-silenced cells partially restore gefitinib sensitivity. Mechanistically, we demonstrate that DDX17 disassociates the E-cadherin/β-catenin complex, resulting in β-catenin nuclear translocation and subsequently augmenting the transcription of β-catenin target genes. Moreover, we identify two nuclear localization signal (NLS) and four nuclear export signal (NES) sequences mediated DDX17 nucleocytoplasmic shuttling via an exportin/importin-dependent pathways. Interruption of dynamic nucleocytoplasmic shuttling of DDX17 impairs DDX17-mediating the activation of β-catenin and acquired resistance in NSCLC cells. In conclusion, our findings reveal a novel and important mechanism by which DDX17 contributes to acquired gefitinib resistance through exportin/importin-dependent cytoplasmic shuttling and followed by activation of β-catenin, and DDX17 inhibition may be a promising strategy to overcome acquired resistance of gefitinib in NSCLC patients.
authors.affiliation: Lab of Experimental Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China.
authors.forename: Chunfen
authors.initials: C
authors.lastname: Mo
authors.affiliation: Lab of Experimental Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.
authors.forename: Di
authors.initials: D
authors.lastname: Gong
authors.affiliation: Lab of Cancer Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Lab of Cancer Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Lab of Experimental Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Lab of Experimental Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Lugang
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Cancer Research, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK.
authors.forename: Frances V
authors.initials: FV
authors.lastname: Fuller-Pace
authors.affiliation: Lab of Experimental Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China. Electronic address: linping@scu.edu.cn.
authors.forename: Ping
authors.initials: P
authors.lastname: Lin
authors.affiliation: Lab of Cancer Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
mesh_terms: D000072283:A549 Cells; D021581:Active Transport, Cell Nucleus; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D051176:beta Catenin; C512478:EGFR protein, human; D066246:ErbB Receptors; C102004:DDX17 protein, human; D053487:DEAD-box RNA Helicases; D000077156:Gefitinib
keywords: Chemoresistance; DDX17; Non-small cell lung cancer; Nucleocytoplasmic shuttle; β-catenin