ArticleCell death & disease2022
Limiting glutamine utilization activates a GCN2/TRAIL-R2/Caspase-8 apoptotic pathway in glutamine-addicted tumor cells.
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 12 papers.
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Who cites it
12 citing papers in PubMed, 17 citations in OpenAlex.
- Unraveling the role of glutamine metabolism in cancer: from cell death mechanisms to tumor microenvironment modulation.Experimental hematology & oncology · 2026Review
- Article
- Metabolic Imaging and Molecular Signatures Reveal Metabolic Phenotypes in Recurrent Glioblastoma.Journal of nuclear medicine : official publication, Society of Nuclear Medicine · 2026Article
- Senescent Stroma-Derived Glutamine: A Driver of Aggressiveness in Prostate and Ovarian Cancer Cells.Cells · 2026Article
- Glutaminase inhibition ameliorates cancer-associated fibroblast lipid support of pancreatic cancer cell growth.Cancer & metabolism · 2025Article
- Activation of the integrated stress response and loss of cFLIPCell death discovery · 2025Article
- Targeting glutamine metabolism as a potential target for cancer treatment.Journal of experimental & clinical cancer research : CR · 2025Review
- Mechanism of calcitonin gene related peptide against acute pancreatitis in rats by modulating amino acid metabolism based on metabonomics.Scientific reports · 2025Article
- Glutamine-mediated epigenetic regulation of cFLIP underlies resistance to TRAIL in pancreatic cancer.Experimental & molecular medicine · 2024Article
- Article
- Multiple Roles of the Stress Sensor GCN2 in Immune Cells.International journal of molecular sciences · 2023Review
- The integrated stress response in cancer progression: a force for plasticity and resistance.Frontiers in oncology · 2023Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Oncogenic transformation leads to changes in glutamine metabolism that make transformed cells highly dependent on glutamine for anabolic growth and survival. Herein, we investigated the cell death mechanism activated in glutamine-addicted tumor cells in response to the limitation of glutamine metabolism. We show that glutamine starvation triggers a FADD and caspase-8-dependent and mitochondria-operated apoptotic program in tumor cells that involves the pro-apoptotic TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), but is independent of its cognate ligand TRAIL. In glutamine-depleted tumor cells, activation of the amino acid-sensing general control nonderepressible-2 kinase (GCN2) is responsible for TRAIL-R2 upregulation, caspase-8 activation, and apoptotic cell death. Interestingly, GCN2-dependent ISR signaling induced by methionine starvation also leads to TRAIL-R2 upregulation and apoptosis. Moreover, pharmacological inhibition of transaminases activates a GCN2 and TRAIL-R2-dependent apoptotic mechanism that is inhibited by non-essential amino acids (NEAA). In addition, metabolic stress upon glutamine deprivation also results in GCN2-independent FLICE-inhibitory protein (FLIP) downregulation facilitating caspase-8 activation and apoptosis. Importantly, downregulation of the long FLIP splice form (FLIP
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