Furthermore, two cell lines (H1975 and H1975/p53KO) demonstrated the different mechanisms of acquired resistance to osimertinib. Secondly, p53 silencing in H1975 cells enhanced the sensitivity to osimertinib through the emergence of mesenchymal-to-epithelial transition, and the emergence of acquired resistance to osimertinib in p53 knockout cells was much slower than in H1975 cells. Firstly, p53 silencing did not affect primary and acquired resistance to EGFR-TKIs in PC-9 cells, but it led to primary resistance to EGFR-TKIs through AXL induction in HCC827 cells. Changes in p53 status affected primary sensitivity as well as acquired resistance to EGFR-TKIs according to cell type. We investigated EMT-related molecules, morphologic changes, and AXL induction to elucidate mechanisms of acquired resistance to EGFR-TKIs according to p53 status. Changes in sensitivity to EGFR-TKIs were determined using p53 overexpression or knockdown in cells with activating EGFR mutations. We investigated the effects of p53 in primary sensitivity and acquired resistance to EGFR-TKIs in NSCLC cells. The emergence of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) with activating EGFR mutations is a major hindrance to treatment. This study indicates that A元55338 confers an aggressive phenotype to NSCLC, and targeting it might be an effective therapeutic strategy. Furthermore, A元55338 was capable of modulating ENO1/EGFR complex interaction and further activating EGFR-AKT signaling. A positive correlation was observed between A元55338 and ENO1 in NSCLC, and ENO1 was subsequently confirmed to be responsible for the oncogenic role of A元55338. Mechanistic investigations showed that A元55338 directly bound with alpha-enolase (ENO1) and enhanced the protein’s stability by modulating its degradation and ubiquitination. Functional assays revealed that A元55338 was critical for promoting aerobic glycolysis and NSCLC progression. Co-immunoprecipitation, in situ proximity ligation assays and western blotting were applied to define the potential downstream pathways of A元55338.Ī元55338 was an upregulated glycolysis-associated lncRNA in NSCLC. Moreover, RNA pull-down, mass spectrometry and RNA immunoprecipitation (RIP) assays were used to identify the protein interacted with A元55338. The biological role of A元55338 on NSCLC cells were evaluated by functional experiments in vitro and in vivo. The transcript abundance of A元55338 in 80 pairs of clinical samples was evaluated by quantitative real-time PCR assay and fluorescence in situ hybridization. To identify glycolysis-associated-lncRNAs in NSCLC, we compared RNA-sequencing results between high ¹⁸F-fluorodeoxyglucose (FDG)-uptake NSCLC tissues and paired paratumor tissues. Recent studies suggest that some dysregulated long non-coding RNAs (lncRNAs) play important roles in tumor metabolic reprogramming.
Abnormal metabolism is a hallmark of cancer however, the mechanism of glycolysis regulation in NSCLC progression is not completely understood. Non-small cell lung cancer (NSCLC) is a malignancy with considerable morbidity and mortality. This review was completed by searching for keywords including 'glutamine', 'NSCLC' and 'therapy' on PubMed, and screening out articles. It also puts forward the concept of combination therapy and patient stratification with the aim of comprehensively showing the effect and prospect of targeted glutamine metabolism in NSCLC therapy. This review not only summarizes the significance of glutamine metabolism in NSCLC cells, but also enumerates traditional glutamine inhibitors along with new targets. In this perspective, the present review aims to provide a new therapeutic strategy of NSCLC through inhibiting the metabolism of glutamine. Glutamine is crucial in non-small cell lung cancer (NSCLC) cells and serves an important role in supporting cell growth, activating signal transduction and maintaining redox homeostasis. Glutamine is the most abundant non-essential amino acid in the circulation, and along with glucose, comprise the two basic nutrients of cancer cell metabolism. The flexible metabolism of cancer cells, which is the result of metabolic reprogramming, can meet the basic needs of cells, even in a nutrition-deficient environment. It is requisite to further explore cancer metabolism, as it helps to simultaneously explain the process of carcinogenesis and guide therapy. The Warburg effect indicates that cancer cells survive through glycolysis under aerobic conditions as such, the topic of cancer metabolism has aroused interest.
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