Abstract
To better understand the resistance mechanism of non-small cell lung cancers (NSCLCs) to gefitinib, the metabolic profiles of gefitinib-resistant A549 cells and gefitinib-sensitive PC-9 cells were analyzed with a metabolomics analytical platform. A549 and PC-9 cells exhibited significant differences in the levels of glutamine-related metabolites. After gefitinib treatment, the glutamine level decreased in A549 cells but showed no change in PC-9 cells. The glutamine consumed by A549 cells was used to generate ATP and glutathione (GSH). As glutamine utilization was suppressed in gefitinib-treated PC-9 cells, the resulting ATP shortage and ROS accumulation led to cell death. The difference in glutamine metabolism was caused by differential changes in the levels of glutamine synthetase (GS, encoded by glutamate-ammonia ligase (GLUL)). GLUL expression was upregulated in gefitinib-sensitive cells, but it was either absent from gefitinib-resistant cells or no significant change was observed in the gefitinib-treated cells. GLUL overexpression in A549 cells significant sensitized them to gefitinib and decreased their invasive capacity. Conversely, knockout GS in PC-9 cells reduced gefitinib sensitivity and enhanced metastasis. Furthermore, the continuous exposure of gefitinib-sensitive HCC827 cells to gefitinib created gefitinib-resistant (GR) HCC827 cells, which exhibited a GLUL deletion and resistance to gefitinib. Thus, GLUL plays a vital role in determining the sensitivity of NSCLCs to gefitinib. Elevated GS levels mediate increased glutamine anabolism, and this novel mechanism sensitizes NSCLCs to gefitinib. The inhibition of glutamine utilization may serve as a potential therapeutic strategy to overcome gefitinib resistance in the clinic.
Highlights
Gefitinib is an inhibitor of epidermal growth factor receptor (EGFR) kinase, which was approved as a first-line treatment for non-small cell lung cancers (NSCLCs) in 2015, only 10% of patients benefit from it[1]
EGFR-mutant PC-9 cells and EGFRwild-type A549 cells were selected as representative gefitinib-sensitive and gefitinib-resistant NSCLCs, respectively
By analyzing the 1H-NMR profiles of different acute myeloid leukemia (AML) cells treated with a combination of bezafibrate and medroxyprogesterone acetate, Tiziani et al.[23] showed that the unexpected antileukemic activities of this combination against AML were associated with reactive oxygen species (ROS) generation rather than an unexpected mechanism
Summary
Gefitinib is an inhibitor of epidermal growth factor receptor (EGFR) kinase, which was approved as a first-line treatment for NSCLC in 2015, only 10% of patients benefit from it[1]. Many factors, such as gender, Official journal of the Cell Death Differentiation Association. The inhibitor of hexokinase II 3-bromopyruvate (3-BrPA) effectively inhibits glycolysis and induces cell death. By tracing metabolic changes, metabolomics approaches are widely used in discovering resistant mechanisms of drugs, providing new insights into pharmacodynamic properties, and elucidating the mechanisms responsible for individual variations in drug response[5,7]
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