ArticleCell death & disease2022
Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 29 citations in OpenAlex.
- Article
- ATF4: Orchestrating Cellular Stress Adaptation, Metabolism, and Immune Regulation in Health and Disease.International journal of molecular sciences · 2026Review
- Metabolic heterogeneity in tumor cells impacts immunology in lung squamous cell carcinoma.Oncoimmunology · 2025Article
- Title: Resveratrol ameliorates liver fibrosis by inhibiting ATF4 to regulate glutamine metabolism in hepatic stellate cells.Archives of pharmacal research · 2025Article
- SLC6A14-mediated glutamine promotes SYTL4-CXCL8 axis activation to drive gemcitabine resistance and immune evasion in pancreatic cancer.Experimental & molecular medicine · 2025Article
- Liquid biopsy diagnostics for non-small cell lung cancer via elucidation of tRNA signatures.Communications medicine · 2025Article
- Recent advances in ASCT2 inhibitors: ligand design and therapeutic applications.Future medicinal chemistry · 2025Review
- ATF4 promotes glutaminolysis and glycolysis in colorectal cancer by transcriptionally inducing SLC1A5.Acta biochimica et biophysica Sinica · 2025Article
- Cholesterol confers resistance to Apatinib-mediated ferroptosis in gastric cancer.Cell & bioscience · 2025Article
- Targeting glutamine metabolism as a potential target for cancer treatment.Journal of experimental & clinical cancer research : CR · 2025Review
- Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives.Signal transduction and targeted therapy · 2025Review
- Inhibition of GLS1 and ASCT2 Synergistically Enhances the Anticancer Effects in Pancreatic Cancer Cells.Journal of microbiology and biotechnology · 2025Article
- Glutamine's double-edged sword: fueling tumor growth and offering therapeutic hope.Frontiers in immunology · 2025Review
- Multifaceted role of GCN2 in tumor adaptation and therapeutic targeting.Translational oncology · 2024Review
- The Cancer Antioxidant Regulation System in Therapeutic Resistance.Antioxidants (Basel, Switzerland) · 2024Review
- Article
- Liquid biopsy techniques and lung cancer: diagnosis, monitoring and evaluation.Journal of experimental & clinical cancer research : CR · 2024Review
- ALYREF-JunD-SLC7A5 axis promotes pancreatic ductal adenocarcinoma progression through epitranscriptome-metabolism reprogramming and immune evasion.Cell death discovery · 2024Article
- Emerging roles of small extracellular vesicles in metabolic reprogramming and drug resistance in cancers.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid metabolic reprogramming.Acta pharmacologica Sinica · 2023Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The efficacy of apatinib has been confirmed in the treatment of solid tumors, including non-small-cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by apatinib and the precise mechanisms of drug resistance are largely unknown. In this study, we demonstrated that apatinib could reprogram glutamine metabolism in human NSCLC via a mechanism involved in amino acid metabolic imbalances. Apatinib repressed the expression of GLS1, the initial and rate-limiting enzyme of glutamine catabolism. However, the broken metabolic balance led to the activation of the amino acid response (AAR) pathway, known as the GCN2/eIF2α/ATF4 pathway. Moreover, activation of ATF4 was responsible for the induction of SLC1A5 and ASNS, which promoted the consumption and metabolization of glutamine. Interestingly, the combination of apatinib and ATF4 silencing abolished glutamine metabolism in NSCLC cells. Moreover, knockdown of ATF4 enhanced the antitumor effect of apatinib both in vitro and in vivo. In summary, this study showed that apatinib could reprogram glutamine metabolism through the activation of the AAR pathway in human NSCLC cells and indicated that targeting ATF4 is a potential therapeutic strategy for relieving apatinib resistance.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.