抑制AKT通路对埃克替尼耐药的非小细胞肺癌细胞迁移能力的影响
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摘要
目的探讨抑制AKT通路对埃克替尼耐药的非小细胞肺癌细胞迁移能力的影响。方法采取持续暴露并逐渐增加药物浓度方法筛选建立耐药细胞系,MTT法检测细胞增殖能力,Transwell法检测细胞迁移能力,Western blotting检测蛋白表达。结果耐药细胞PC9/IcoR迁移能力高于PC9细胞(P <0.05);PC9/IcoR细胞表皮生长因子受体及AKT磷酸化水平明显高于PC9细胞(P <0.05);LY294002抑制AKT活化后PC9/IcoR细胞迁移能力明显下降(P <0.05)。结论抑制AKT通路可以抑制埃克替尼耐药的非小细胞肺癌细胞迁移。
Objective To investigate the effect of AKT pathway inhibition on the migration of PC9/IcoR cells. Methods The icotinib resistant cell line was established through continuous exposure of PC9 cells to gradually increasing concentrations of the drug. Cell proliferation,protein expression,and cell migration were analyzed through MTT assay,Western blotting,and Transwell assay,respectively. Results The migration ability of drug-resistant PC9/IcoR cells was higher than that of PC9 cells(P < 0.05). The expression levels of the phospho-epidermal growth factor receptor(p-EGFR) and phospho-AKT were higher in PC9/IcoR cells than in PC9 cells(P < 0.05). Inhibition of the AKT pathway using LY294002 significantly decreased the migration ability of the PC9/IcoR cells(P < 0.05). Conclusion Inhibition of the AKT pathway could inhibit the migration of icotinib-resistant non-small-cell lung cancer cells.
Objective To investigate the effect of AKT pathway inhibition on the migration of PC9/IcoR cells. Methods The icotinib resistant cell line was established through continuous exposure of PC9 cells to gradually increasing concentrations of the drug. Cell proliferation,protein expression,and cell migration were analyzed through MTT assay,Western blotting,and Transwell assay,respectively. Results The migration ability of drug-resistant PC9/IcoR cells was higher than that of PC9 cells(P < 0.05). The expression levels of the phospho-epidermal growth factor receptor(p-EGFR) and phospho-AKT were higher in PC9/IcoR cells than in PC9 cells(P < 0.05). Inhibition of the AKT pathway using LY294002 significantly decreased the migration ability of the PC9/IcoR cells(P < 0.05). Conclusion Inhibition of the AKT pathway could inhibit the migration of icotinib-resistant non-small-cell lung cancer cells.
引文
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[3]TAN CS,GILLIGAN D,PACEY S.Treatment approaches for EG-FR-inhibitor-resistant patients with non-small-cell lung cancer[J].Lancet Oncol,2015,16(9):e447-e459.DOI:10.1016/S1470-2045(15)00246-6.
[4]GUPTA GP,MASSAGUE J.Cancer metastasis:building a framework[J].Cell,2006,127(4):679-695.DOI:10.1016/j.cell.2006.11.001.
[5]TANG ZH,JIANG XM,GUO X,et al.Characterization of osimertinib(AZD9291)-resistant non-small cell lung cancer NCI-H1975/OSIRcell line[J].Oncotarget,2016,7(49):81598-81610.DOI:10.18632/oncotarget.13150.
[6]LI L,GU X,YUE J,et al.Acquisition of EGFR TKI resistance and EMT phenotype is linked with activation of IGF1R/NF-κB pathway in EGFR-mutant NSCLC[J].Oncotarget,2017,8(54):92240-92253.DOI:10.18632/oncotarget.21170.
[7]ZHANG F,WANG J,WANG X,et al.CD146-mediated acquisition of stemness phenotype enhances tumour invasion and metastasis after EGFR-TKI resistance in lung cancer[J].Clin Respir J,2019,13(1):23-33.DOI:10.1111/crj.12976.
[8]WANG L,DONG X,REN Y,et al.Targeting EHMT2 reverses EG-FR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway[J].Cell Death Dis,2018,9(2):129.DOI:10.1038/s41419-017-0120-6.
[9]ZHAI Y,ZHANG Y,NAN K,et al.Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib[J].Oncol Lett,2017,13(5):3233-3238.DOI:10.3892/ol.2017.5829.
[10]ZHANG T,ZHENG C,HOU K,et al.Suppressed expression of Cbl-b by NF-κB mediates icotinib resistance in EGFR-mutant nonsmall-cell lung cancer[J].Cell Biol Int,2019,43(2):98-107.DOI:10.1002/cbin.11026.
[11]CHIANG AC,MASSAGU J.Molecular basis of metastasis[J].NEngl J Med,2008,359(26):2814-2823.DOI:10.1056/NEJM-ra0805239.
[12]PRIETO-GARC A E,D AZ-GARC A CV,GARC A-RUIZ L,et al.Epithelial-to-mesenchymal transition in tumor progression[J].Med Oncol,2017,34(7):122.DOI:10.1007/s12032-017-0980-8.
[13]CHIOU SH,WANG ML,CHOU YT,et al.Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation[J].Cancer Res,2010,70(24):10433-10444.DOI:10.1158/0008-5472.CAN-10-2638.
[14]BYERS LA,DIAO L,WANG J,et al.An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3Kinhibitors and identifies AXL as a therapeutic target for overcoming EGFR inhibitor resistance[J].Clin Cancer Res,2013,19(1):279-290.DOI:10.1158/1078-0432.CCR-12-1558.
[15]KING D,YEOMANSON D,BRYANT HE.PI3King the lock:targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma[J].J Pediatr Hematol Oncol,2015,37(4):245-251.DOI:10.1097/MPH.0000000000000329.
[16]YOELI-LERNER M,YIU GK,RABINOVITZ I,et al.AKT blocks breast cancer cell motility and invasion through the transcription factor NFAT[J].Mol Cell,2005,20(4):539-550.DOI:10.1016/j.molcel.2005.10.033.
[17]HUANG LH,FU LW.Mechanisms of resistance to EGFR tyrosine kinase inhibitors[J].Acta Pharm Sini B,2015,5(5):390-401.DOI:10.1016/j.apsb.2015.07.001.
[18]CHEN KF,CHEN HL,TAI WT,et al.Activation of phosphatidylinositol 3-kinase/AKT signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells[J].J Pharmacol Exp Ther,2011,337(1):155-161.DOI:10.1124/jpet.110.175786.
[19]DONEV IS,WANG W,YAMADA T,et al.Transient PI3K inhibition induces apoptosis and overcomes HGF-mediated resistance to EG-FRTKIs in EGFR mutant lung cancer[J].Clin Cancer Res,2011,17(8):2260-2269.DOI:10.1158/1078-0432.CCR-10-1993.
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