FGL1 regulates acquired resistance to Gefitinib by inhibiting apoptosis in non-small cell lung cancer

Abstract

Background: This study investigated the role of fibrinogen-like protein 1 (FGL1) in regulating gefitinib resistance of PC9/GR non-small cell lung cancer (NSCLC). Methods: The effect of different concentrations of gefitinib on cell proliferation were evaluated using the CCK-8 assay. FGL1 expression in the normal human bronchial epithelial cell line Beas-2B, as well as four lung tumor cell lines, H1975, A549, PC9, and PC9/GR, was investigated by using western blotting and qRT-PCR. FGL1 was knocked down using small interfering RNA to evaluate the effects of FGL1 on PC9 and PC9/GR. The correlation between FGL1 expression and gefitinib resistance was determined in vitro via CCK-8 and colony formation assays, and flow cytometry and in vivo via flow cytometry and immunohistochemistry. Results: FGL1 expression was significantly upregulated in non-small cell lung cancer cells with EGFR mutation and higher in the gefitinib-resistant NSCLC cell line PC9/GR than in the gefitinib-sensitive NSCLC cell line PC9. Further, FGL1 expression in PC9 and PC9/GR cells increased in response to gefitinib treatment in a dose-dependent manner. Knockdown of FGL1 suppressed cell viability, reduced the gefitinib IC50 value, and enhanced apoptosis in PC9 and PC9/GR cells upon gefitinib treatment. Mouse xenograft experiments showed that FGL1 knockdown in PC9/GR tumor cells enhanced the inhibitory and apoptosis-inducing actions of gefitinib. The potential mechanism of gefitinib in inducing apoptosis of PC9/GR cells involves inhibition of PARP1 and caspase 3 expression via suppression of FGL1. Conclusions: FGL1 confers gefitinib resistance in the NSCLC cell line PC9/GR by regulating the PARP1/caspase 3 pathway. Hence, FGL1 is a potential therapeutic target to improve the treatment response of NSCLC patients with acquired resistance to gefitinib.

Fibrinogen-Like Protein 1 Modulates Sorafenib Resistance in Human Hepatocellular Carcinoma Cells

“…Further, Bie et al reported, via through TCGA and GEO database data mining and in vitro functional experiments, that the loss of FGL1 promotes cell growth, epithelial-mesenchymal transition (EMT), and angiogenesis in LKB1-mutant lung adenocarcinoma [ 24 ]. However, Sun et al reported that FGL1 confers gefitinib resistance and that the knockdown of FGL1 in lung adenocarcinoma cells induces antitumor effects in vivo [ 36 ]. Therefore, further preclinical and clinical studies of HCC are necessary to clarify the role of FGL1 and its impact on HCC.…”

The role of Fibrinogen-like proteins in Cancer

“…FGL1 induces insulin resistance through an ERK1/2-dependent pathway in hepatocytes, and induces adipogenesis by stimulating the ERK1/2-C/EBPβ-dependent pathway 16 . Some non-small cell lung cancer (NSCLC) patients are acquired resistance to gefitinib, a drug for NSCLC therapy, Sun et al found that FGL1 was upregulated in gefitinib-resistant cancer cells, and mediated the resistance to gefitinib in NSCLC cells by regulating the PARP1/ Caspase 3 pathway 57 . Lymphocyte activation gene 3 (LAG-3) is a transmembrane protein that is generally expressed on the surface of activated immune cells, such as NK cells, T cells, and other immune cells 58 .…”

“…Meanwhile, FGL1 accelerates the proliferation, migration, and invasion of GC cells, accordingly FGL1 can be used as a target for the treatment of GC and a predictor of the prognosis of GC patients 12 . Gefitinib resistance can be regulated by FGL1 through inhibiting the apoptosis of the non-small cell lung cancer (NSCLC) cell line PC9/GR, and FGL1 can act as a latent therapeutic target for NSCLC 57 . Besides, Chen et al have conducted in-depth studies on the role of FGL1 that they inoculated MC38 (a type of colon cancer cell) through mice and found that the tumor growth of FGL1-KO mice was significantly slower than that of WT mice 15 .…”

A Double-Antibody Sandwich ELISA for Sensitive and Specific Detection of Swine Fibrinogen-Like Protein 1

“…It has been reported that FGL1 confers gefitinib resistance in the NSCLC cell line PC9/GR by regulating the PARP1/caspase 3 pathway. Hence, FGL1 maybe a potential therapeutic target to improve the treatment response of NSCLC patients with acquired resistance to gefitinib (11). Also, It is found that the plasma FGL1 concentrations were significantly higher in the obese group than those in the normal weight group and FGL1 may induce adipogenesis through an ERK1/2-C/EBPb-dependent pathway in 3T3-L1 adipocytes.…”