Gefitinib promotes CXCR4‑dependent epithelial to mesenchymal transition via TGF‑β1 signaling pathway in lung cancer cells harboring EGFR mutation
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Q. Zhu [1] ; Z. Zhang [2] ; C. Lu [1] ; F. Xu [1] ; W. Mao [1] ; K. Zhang [1] ; H. Shou [1] ; Z. Liu [1] ; J. Gu [1] ; D. Ge [1]
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[1] Zhongshan Hospital
Zhongshan Hospital
China
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[2] Department of Thoracic Surgery, The Central Hospital of Xuhui District, Shanghai, People’s Republic of China
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- Localización: Clinical & translational oncology, ISSN 1699-048X, Vol. 22, Nº. 8, 2020, págs. 1355-1363
- Idioma: inglés
- Texto completo no disponible (Saber más ...)
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Resumen
Purpose Epithelial to mesenchymal transition (EMT) plays an important role in acquired resistance to gefitinib in lung cancer. This study aimed to explore the underlying mechanism of gefitinib-induced EMT in lung adenocarcinoma cells harboring EGFR mutation.
Methods CXC chemokine receptor 4 (CXCR4) expression was determined through qRT-PCR, Western blot and flow cytom- etry assays in lung cancer cell line (PC9) bearing mutated EGFR . Functional role of CXCR4 was inhibited applying siRNAs as well as the specific antagonist AMD3100. The expression of EMT markers was determined, and the migration of PC9 cells was measured with transwell assay.
Results We found that gefitinib promoted the migratory capacity of PC9 cells in vitro, which correlated with EMT occur - rence through upregulation of CXCR4. Blocking CXCR4 significantly suppressed gefitinib-induced enhancement of migra- tion and EMT. Moreover, we determined that the upregulation of CXCR4 by gefitinib was dependent on TGF-β1/Smad2 signaling activity.
Conclusions Our study suggested a potential mechanism by which gefitinib induced EMT in cells harboring EGFR mutation through a pathway involving TGF-β1 and CXCR4. Thus, the combination of CXCR4 antagonist and TGFβR inhibitors might provide an alternative strategy to overcome progression of lung cancer after gefitinib treatment.
