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Reelin Promotes Cisplatin Resistance by Induction of Epithelial-Mesenchymal Transition via p38/GSK3β/Snail Signaling in Non-Small Cell Lung Cancer

Ji-Min Li, Fang Yang, Juan Li, Wei-Qi Yuan, Hao Wang, Yi-Qin Luo

Department of Laboratory Medicine, The Affiliated Anhui Provincial Hospital of Anhui Medical University, Hefei, Anhui, China (mainland)

Med Sci Monit 2020; 26:e925298

DOI: 10.12659/MSM.925298

Available online: 2020-06-12

Published: 2020-08-07

BACKGROUND: Emerging evidence suggests the involvement of Reelin in chemoresistance in various cancers. However, its function in cisplatin (DDP) sensitivity of non-small cell lung cancer (NSCLC) needs to be investigated.
MATERIAL AND METHODS: Reelin expression in cisplatin-sensitive A549 cells and cisplatin-resistant NSCLC (A549/DDP) cells was analyzed by western blot analysis. qRT-PCR, western blotting, immunofluorescence, CCK-8 assays, Annexin V/propidium iodide apoptosis assay, and Transwell migration assays were carried out to determine the function of Reelin on DDP resistance.
RESULTS: Reelin was markedly increased in A549/DDP cells relative to A549 cells. Knockdown of Reelin enhanced DDP chemosensitivity of A549/DDP cells, whereas overexpression of Reelin enhanced DDP resistance of A549, H1299, and H460 cells. Reelin induced DDP resistance in NSCLC cells via facilitating epithelial-mesenchymal transition (EMT). Furthermore, Reelin modulated p38/GSK3ß signal transduction and promoted Snail (EMT-associated transcription factor) expression. Suppression of p38/Snail reversed Reelin-induced EMT and resistance of NSCLC cells to DDP.
CONCLUSIONS: These data indicated that Reelin induces DDP resistance of NSCLC by regulation of the p38/GSK3ß/Snail/EMT signaling pathway and provide evidence that Reelin suppression can be an effective strategy to suppress DDP resistance in NSCLC.

Keywords: Cisplatin, Epithelial-mesenchymal transition, Gait Disorders, Neurologic, MAP Kinase Signaling System