International immunopharmacology · 2025
ELK3-SERPINE1-PCBP2 axis promotes gefitinib resistance in lung cancer by inhibiting ferroptosis.
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Zhu Xunxia, Wei Jionglin, Chen Xiaoyu, Zhang Xuelin, Li Zheng, Yang Fuzhi, Jiang Shuai, Yang Zhengyao, Ge Haiyan, Shen Xiaoyong
Аннотация
OBJECTIVE: To investigate the role and mechanism of SERPINE1 in gefitinib (GEF) resistance in lung cancer and to identify a novel therapeutic target for overcoming chemoresistance.
METHODS: GEF-resistant (GR) cell lines PC-9/GR and HCC827/GR were established. Cell viability, proliferation, death, migration, and invasion were assessed using CCK-8, colony formation, Calcein-AM/PI staining, and Transwell assays. Gene and protein expression were determined by RT-qPCR and Western blot. Transcriptional regulation was verified via ChIP-qPCR and dual-luciferase reporter assays, respectively. Protein-protein interactions were screened via co-immunoprecipitation and LC-MS/MS. The molecular mechanism was further elucidated using ubiquitination and protein stability assays. Ferroptosis-related indicators were evaluated by measuring intracellular Fe2+, lipid peroxidation, malondialdehyde, and immunohistochemistry. A mouse xenograft model was established to validate the findings in vivo.
RESULTS: SERPINE1 expression was elevated in GR lung cancer cells and correlated with poor patient prognosis. SERPINE1 knockdown reduced the half-maximal inhibitory concentration of GEF in resistant cells, while also inhibiting cellular proliferation, migration, and invasion, and promoting cell death. ELK3 was identified as an upstream transcription factor promoting SERPINE1 transcriptional activity. Furthermore, ELK3-mediated GEF resistance was dependent on SERPINE1. SERPINE1 maintained PCBP2 protein stability by inhibiting its ubiquitination and subsequent lysosomal degradation. PCBP2 overexpression suppressed ferroptosis and enhanced GEF resistance. In vivo experiments demonstrated that knockdown of SERPINE1 inhibited tumor growth and enhanced the antitumor efficacy of GEF, whereas overexpression of PCBP2 reversed this effect.
CONCLUSION: The ELK3-SERPINE1-PCBP2 axis promotes GEF resistance in lung cancer by inhibiting ferroptosis, providing a potential new therapeutic strategy for overcoming chemoresistance.
METHODS: GEF-resistant (GR) cell lines PC-9/GR and HCC827/GR were established. Cell viability, proliferation, death, migration, and invasion were assessed using CCK-8, colony formation, Calcein-AM/PI staining, and Transwell assays. Gene and protein expression were determined by RT-qPCR and Western blot. Transcriptional regulation was verified via ChIP-qPCR and dual-luciferase reporter assays, respectively. Protein-protein interactions were screened via co-immunoprecipitation and LC-MS/MS. The molecular mechanism was further elucidated using ubiquitination and protein stability assays. Ferroptosis-related indicators were evaluated by measuring intracellular Fe2+, lipid peroxidation, malondialdehyde, and immunohistochemistry. A mouse xenograft model was established to validate the findings in vivo.
RESULTS: SERPINE1 expression was elevated in GR lung cancer cells and correlated with poor patient prognosis. SERPINE1 knockdown reduced the half-maximal inhibitory concentration of GEF in resistant cells, while also inhibiting cellular proliferation, migration, and invasion, and promoting cell death. ELK3 was identified as an upstream transcription factor promoting SERPINE1 transcriptional activity. Furthermore, ELK3-mediated GEF resistance was dependent on SERPINE1. SERPINE1 maintained PCBP2 protein stability by inhibiting its ubiquitination and subsequent lysosomal degradation. PCBP2 overexpression suppressed ferroptosis and enhanced GEF resistance. In vivo experiments demonstrated that knockdown of SERPINE1 inhibited tumor growth and enhanced the antitumor efficacy of GEF, whereas overexpression of PCBP2 reversed this effect.
CONCLUSION: The ELK3-SERPINE1-PCBP2 axis promotes GEF resistance in lung cancer by inhibiting ferroptosis, providing a potential new therapeutic strategy for overcoming chemoresistance.
Предметные рубрики MeSH
HumansFerroptosisAnimalsDrug Resistance, NeoplasmGefitinibLung NeoplasmsPlasminogen Activator Inhibitor 1MiceCell Line, TumorAntineoplastic AgentsRNA-Binding ProteinsMice, NudeCell ProliferationMice, Inbred BALB CCell MovementXenograft Model Antitumor AssaysFemaleProto-Oncogene Proteins c-etsGene Expression Regulation, NeoplasticMale