CCL2 promotes EGFR-TKIs resistance in non-small cell lung cancer via the AKT-EMT pathway  

作　　者：Yunlian Diao Shibo Huang Fangpeng Liu Shu Liao Chenxi Guan Xiaojian Xiong Ping Zhang Junyao Li Wei Zhang Ying Ying 

机构地区：[1]Jiangxi Provincial Key Laboratory of Prevention and Treatment of Infectious Diseases,Jiangxi Medical Center for Major Public Health Events,the First Affiliated Hospital,Jiangxi Medical College,Nanchang University,Nanchang 330006,China [2]Jiangxi Provincial Key Laboratory of Respiratory Diseases,Jiangxi Institute of Respiratory Disease,Department of Respiratory and Critical Care Medicine,the First Affiliated Hospital,Jiangxi Medical College,Nanchang University,Nanchang 330006,China [3]The Clinical Trial Research Center,the First Affiliated Hospital,Jiangxi Medical College,Nanchang University,Nanchang 330006,China [4]Department of Physiology,School of Basic Medical Sciences,Jiangxi Medical College,Nanchang University,Nanchang 330006,China

出　　处：《Acta Biochimica et Biophysica Sinica》2024年第10期1549-1560,共12页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the National Natural Science Foundation of China(No.82060424);the Natural Science Foundation of Jiangxi Province(No.20232BAB206163);the Youth Research and Innovation Fund of the First Affiliated Hospital of Nanchang University(No.YFYPY202204).

摘　　要：Acquired resistance to EGFR tyrosine kinase inhibitors(EGFR-TKIs)represents a primary cause of treatment failure in non-small cell lung cancer(NSCLC)patients.Chemokine(C-C motif)ligand 2(CCL2)is recently found to play a pivotal role in determining anti-cancer treatment response.However,the role and mechanism of CCL2 in the development of EGFR-TKIs resistance have not been fully elucidated.In the present study,we focus on the function of CCL2 in the development of acquired resistance to EGFR-TKIs in NSCLC cells.Our results show that CCL2 is aberrantly upregulated in EGFR-TKIs-resistant NSCLC cells and that CCL2 overexpression significantly diminishes sensitivity to EGFR-TKIs.Conversely,CCL2 suppression by CCL2 synthesis inhibitor,bindarit,or CCL2 knockdown can reverse this resistance.CCL2 upregulation can also lead to enhanced migration and increased expressions of epithelial-mesenchymal transition(EMT)markers in EGFR-TKI-resistant NSCLC cells,which could also be rescued by CCL2 knockdown or inhibition.Furthermore,our findings suggest that CCL2-dependent EGFR-TKIs resistance involves the AKT-EMT signaling pathway;inhibition of this pathway effectively attenuates CCL2-induced cell migration and EMT marker expression.In summary,CCL2 promotes the development of acquired EGFR-TKIs resistance and EMT while activating AKT signaling in NSCLC.These insights suggest a promising avenue for the development of CCL2-targeted therapies that prevent EGFR-TKIs resistance in NSCLC.

关 键 词：EGFR-TKIs resistance non-small cell lung cancer CCL2 epithelial-mesenchymal transition 

分 类 号：R734.2[医药卫生—肿瘤]