| Overexpression of CXCR4 induces resistance to gefitinib in lung adenocarcinoma cells via enhancing lactate dehydrogenase A phosphorylation |
| Received:January 12, 2021 Revised:March 21, 2021 Click here to download the full text |
| Citation of this paper:ZHU Qiao-liang,LU Chun-lai,GU Jie,GE Di.Overexpression of CXCR4 induces resistance to gefitinib in lung adenocarcinoma cells via enhancing lactate dehydrogenase A phosphorylation[J].Chinese Journal of Clinical Medicine,2021,28(3):408-415 |
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| Author Name | Affiliation | E-mail | | ZHU Qiao-liang | Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China | | | LU Chun-lai | Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China | | | GU Jie | Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China | | | GE Di | Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China | Dige6902@163.com |
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| Abstract:Objective: To explore the underlying mechanism of CXC chemokine receptor 4 (CXCR4)-induced resistance to gefitinib in lung adenocarcinoma. Methods: CXCR4 expression of lung adenocarcinoma cells bearing EGFR-19del mutation was detected and modulated with siRNA interference or lentiviral infection. Assays of colony-formation, CCK-8, flow cytometric apoptosis, detection of apoptotic proteins and EGFR downstream signaling molecules, and tumor formation in vivo were conducted to identify gefitinib sensitivity. Co-immunoprecipitation combined with mass spectrometric analysis was applied to screen CXCR4-interacting proteins. Glycolysis levels of cells were detected and glycolysis inhibitors were applied to detect cell functions under gefitinib. Results: PC9/GR cells exhibited significant resistance to gefitinib. The IC50 for gefitinib of PC9/GR cells is nearly 100 times higher than that of PC9 cells (19.15 μmol/L vs 0.195 μmol/L). CXCR4 was overexpressed in PC9/GR cells (more than 4 times higher than that of PC9 cells), and inhibition of CXCR4 sensitized PC9/GR cells to gefitinib. Conversely, overexpressing CXCR4 conferred resistance to PC9 cells, by which the IC50 for gefitinib was increased from 0.89 μmol/L to 10.10 μmol/L. Furthermore, we identified lactate dehydrogenase A as a novel CXCR4 substrate, finding that overexpression of CXCR4 promoted LDHA phosphorylation by which aerobic glycolysis was enhanced. Importantly, CXCR4-induced resistance to gefitinib in lung adenocarcinoma cells could be reversed by glycolysis inhibitors both in vitro and in vivo. Conclusions: CXCR4 overexpression induced resistance to gefitinib in lung adenocarcinoma cells through enhancing glycolysis by promoting LDHA phosphorylation. Combination of CXCR4 antagonist and glycolysis inhibitors might provide an alternative strategy to overcome the progression of lung cancer after gefitinib treatment. |
| keywords:CXC chemokine receptor 4 lactate dehydrogenase A resistance to gefitinib lung adenocarcinoma |
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