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Astragalus polysaccharides reverse gefitinib resistance by inhibiting mesenchymal transformation in lung adenocarcinoma cells.

ABSTRACT: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been used as first-line recommended therapy for EGFR mutant non-small cell lung cancer patients. However, epithelial-mesenchymal transition (EMT) can reduce EGFR-TKI sensitivity and lead to resistance. This study was designed to investigate the reversal effect of astragalus polysaccharides (APS) on gefitinib resistance (GR) and to elucidate the underlying mechanisms. PC9 and HCC827 lung cancer cells were stimulated by TGF-?1 to develop EMT-associated GR cells. Cell proliferation, migration and apoptosis assays were used to confirm the effect of gefitinib on GR cells and the therapeutic effect of APS on GR cells after knockdown and over-expression of related signaling pathways. Reverse transcription polymerase chain reaction, western blotting, and immunofluorescent staining assays were used to evaluate the expression levels of E-cadherin, N-cadherin, vimentin, PD-L1, and SREBP-1. Furthermore, proliferation and migration abilities were enhanced, while apoptosis ability was weakened in EMT-associated GR cells. After over-expression of PD-L1, expression levels of N-cadherin, vimentin and SREBP-1 increased, while expression of E-cadherin decreased. After knockdown of PD-L1 or SREBP-1, E-cadherin expression increased, while expression of N-cadherin and vimentin decreased. Further studies revealed that APS promoted apoptosis and reduced proliferation and migration abilities in GR cells. Moreover, APS increased expression of E-cadherin and decreased expression of N-cadherin and vimentin, indicating that it may be related to inhibition of the PD-L1/SREBP-1/EMT signaling pathway. Based on these findings, it can be concluded that APS can reverse acquired resistance to gefitinib in lung cancer cells by inhibiting the PD-L1/SREBP-1/EMT signaling pathway.

SUBMITTER: Wei J

PROVIDER: S-EPMC7269999 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Astragalus polysaccharides reverse gefitinib resistance by inhibiting mesenchymal transformation in lung adenocarcinoma cells.

Wei Jia J Li Yanmeng Y Xu Bo B Yu Jing J

American journal of translational research 20200515 5

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been used as first-line recommended therapy for EGFR mutant non-small cell lung cancer patients. However, epithelial-mesenchymal transition (EMT) can reduce EGFR-TKI sensitivity and lead to resistance. This study was designed to investigate the reversal effect of astragalus polysaccharides (APS) on gefitinib resistance (GR) and to elucidate the underlying mechanisms. PC9 and HCC827 lung cancer cells were stimulated by T ...[more]

PMID: 32509166

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Project description:Background: Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. In traditional anti-cancer therapy, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) have been proven to be beneficial for patients with EGFR mutations. However, patients with EGFR wild-type NSCLC were usually not respond to EGFR-TKIs. Enhancer of zeste homolog 2 (EZH2) is a key molecular in the PRC2 complex and plays an important role in epigenetic regulation and is overexpressed in variant tumors. EZH2 inhibitors have been reported to sensitize variant tumor cells to anticancer drugs. This study aimed to investigate whether the EZH2 inhibitors, GSK343 and DZNep when combined with gefitinib can reverse EGFR-TKIs resistance in EGFR wild-type NSCLC cells.Methods: The RNA-sequencing data of patients with NSCLC [502 patients with lung squamous cell carcinoma, including 49 paracancerous lung tissues and 513 patients with lung adenocarcinoma (LUAD), including 59 paracancerous lung tissues] from the Cancer Genome Atlas (TCGA), were analyzed for EZH2 expression. EZH2 expression was verified in 40 NSCLC tissue cancer samples and their corresponding paracancerous tissues from our institute (TJMUGH) via RT-PCR. A549 and H1299 cells treated with siRNA or EZH2 inhibitors were subjected to cell viability and apoptosis analyses as well to EGFR pathway proteins expression analyses via western blotting.Results: EZH2 was upregulated in human NSCLC tissues and correlated with poor prognosis in patients with LUAD based on data from both TCGA and TJMUGH. Both GSK343 and DZNep sensitized EGFR wild-type LUAD cells (A549 and H1299) to gefitinib and suppressed cell viability and proliferation in vitro by downregulating the phosphorylation of EGFR and AKT and by inducing cell apoptosis. Co-administration of EZH2 inhibitors (GSK343 or DZNep) with gefitinib exerted a stronger inhibitory effect on tumor activity, cell proliferation and cell migration than single drug administration in vitro and in vivo.Conclusions: These data suggest that the combination of EZH2 inhibitors with EGFR-TKIs may be an effective method for treating NSCLC-patients with EGFR-wild type, who do not want to undergo traditional treatment with chemotherapy.

Project description:Epithelial-mesenchymal transition (EMT) has recently been recognized as a key element of cell invasion, migration, metastasis, and drug resistance in several types of cancer, including non-small cell lung cancer (NSCLC). Our aim was to clarify microRNA (miRNA) -related mechanisms underlying EMT followed by acquired resistance to epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) in NSCLC. MiRNA expression profiles were examined before and after transforming growth factor-beta1 (TGF-β1) exposure in four human adenocarcinoma cell lines with or without EMT. Correlation between expressions of EMT-related miRNAs and resistance to EGFR-TKI gefitinib was evaluated. MiRNA array and quantitative RT-PCR revealed that TGF-β1 significantly induced overexpression of miR-134, miR-487b, and miR-655, which belong to the same cluster located on chromosome 14q32, in lung adenocarcinoma cells with EMT. MAGI2 (membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2), a predicted target of these miRNAs and a scaffold protein required for PTEN (phosphatase and tensin homolog), was diminished in A549 cells with EMT after the TGF-β1 stimulation. Overexpression of miR-134 and miR-487b promoted the EMT phenomenon and affected the drug resistance to gefitinib, whereas knockdown of these miRNAs inhibited the EMT process and reversed TGF-β1-induced resistance to gefitinib. Our study demonstrated that the miR-134/487b/655 cluster contributed to the TGF-β1-induced EMT phenomenon and affected the resistance to gefitinib by directly targeting MAGI2, whose suppression subsequently caused loss of PTEN stability in lung cancer cells. The miR-134/miR-487b/miR-655 cluster may be new therapeutic targets in advanced lung adenocarcinoma patients, depending on the EMT phenomenon. miRNA expression profiles before and after TGF-β1 exposure were assessed in the four lung adenocarcinoma cell lines, A549, LC2/ad, PC3, and, PC9 by TaqMan miRNA arrays. Relative ratios of miRNAs in cells after TGF-β1 exposure were calculated when compared with the cells before TGF-β1 exposure.

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Astragalus polysaccharides reverse gefitinib resistance by inhibiting mesenchymal transformation in lung adenocarcinoma cells.

Publications

Astragalus polysaccharides reverse gefitinib resistance by inhibiting mesenchymal transformation in lung adenocarcinoma cells.

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