ArticleMolecular cancer therapeutics2016
Alkylating Agent-Induced NRF2 Blocks Endoplasmic Reticulum Stress-Mediated Apoptosis via Control of Glutathione Pools and Protein Thiol Homeostasis.
Article in Molecular cancer therapeutics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 68 citations in OpenAlex.
- Genetic variants of TLR4, including the novel variant, rs5030719, and related genes are associated with susceptibility to clinical malaria in African children.Malaria journal · 2023Trial
- Context-dependent NRF2 signaling in cancer: mechanisms and precision modulation.Molecular biology reports · 2026Review
- Cysteine Metabolism in the Control of Oxidative Stress in Cancer, Focusing on Carbon and Sulfur Metabolism.Advances in experimental medicine and biology · 2026Review
- The Interdependence of Carbon Substrates and Metabolic Pathways Enables the Metabolic Plasticity of Cancer Cells.Advances in experimental medicine and biology · 2026Review
- Transcriptomic profiling of human endothelial cells infected with venezuelan equine encephalitis virus reveals NRF2 driven host reprogramming mediated by omaveloxolone treatment.Frontiers in genetics · 2025Article
- Integration of epigenomic and transcriptomic profiling uncovers EZH2 target genes linked to cysteine metabolism in hepatocellular carcinoma.Cell death & disease · 2024Article
- Therapeutic potential of omaveloxolone in counteracting muscle atrophy post-denervation: a multi-omics approach.Journal of translational medicine · 2024Article
- Identification and Validation of Endoplasmic Reticulum Stress-Related Gene in Traumatic Brain Injury.Journal of molecular neuroscience : MN · 2024Article
- p53-Mediated Mitochondrial Translocation of EI24 Triggered by ER Stress Plays an Important Role in Arsenic-Induced Liver Damage via Activating Mitochondrial Apoptotic Pathway.Biological trace element research · 2024Article
- Glutathione: A Key Regulator of Extracellular Matrix and Cell Death in Intervertebral Disc Degeneration.Mediators of inflammation · 2024Review
- Regulation of base excision repair during adipogenesis and osteogenesis of bone marrow-derived mesenchymal stem cells.Scientific reports · 2023Article
- Dibenzoylmethane ameliorates adiposity-mediated neuroinflammatory response and inflammation-mediated neuronal cell death in mouse microglia and neuronal cells.Food science and biotechnology · 2023Article
- Incretin Mimetics Restore the ER-Mitochondrial Axis and Switch Cell Fate Towards Survival in LUHMES Dopaminergic-Like Neurons: Implications for Novel Therapeutic Strategies in Parkinson's Disease.Journal of Parkinson's disease · 2023Article
- PIM1 promotes hepatic conversion by suppressing reprogramming-induced ferroptosis and cell cycle arrest.Nature communications · 2022Article
- Advances in measuring cancer cell metabolism with subcellular resolution.Nature methods · 2022Review
- XAF1 drives apoptotic switch of endoplasmic reticulum stress response through destabilization of GRP78 and CHIP.Cell death & disease · 2022Article
- Good, bad, and neglectful: Astrocyte changes in neurodegenerative disease.Free radical biology & medicine · 2022Review
- A DNA repair-independent role for alkyladenine DNA glycosylase in alkylation-induced unfolded protein response.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology.Nature communications · 2022Article
- The putative role of gut microbiota in cancer: Cysteine is a pivotal coin.Frontiers in gastroenterology (Lausanne, Switzerland) · 2022Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 3 countries.
Funding
Abstract
Alkylating agents are a commonly used cytotoxic class of anticancer drugs. Understanding the mechanisms whereby cells respond to these drugs is key to identify means to improve therapy while reducing toxicity. By integrating genome-wide gene expression profiling, protein analysis, and functional cell validation, we herein demonstrated a direct relationship between NRF2 and Endoplasmic Reticulum (ER) stress pathways in response to alkylating agents, which is coordinated by the availability of glutathione (GSH) pools. GSH is essential for both drug detoxification and protein thiol homeostasis within the ER, thus inhibiting ER stress induction and promoting survival, an effect independent of its antioxidant role. NRF2 accumulation induced by alkylating agents resulted in increased GSH synthesis via GCLC/GCLM enzyme, and interfering with this NRF2 response by either NRF2 knockdown or GCLC/GCLM inhibition with buthionine sulfoximine caused accumulation of damaged proteins within the ER, leading to PERK-dependent apoptosis. Conversely, upregulation of NRF2, through KEAP1 depletion or NRF2-myc overexpression, or increasing GSH levels with N-acetylcysteine or glutathione-ethyl-ester, decreased ER stress and abrogated alkylating agents-induced cell death. Based on these results, we identified a subset of lung and head-and-neck carcinomas with mutations in either KEAP1 or NRF2/NFE2L2 genes that correlate with NRF2 target overexpression and poor survival. In KEAP1-mutant cancer cells, NRF2 knockdown and GSH depletion increased cell sensitivity via ER stress induction in a mechanism specific to alkylating drugs. Overall, we show that the NRF2-GSH influence on ER homeostasis implicates defects in NRF2-GSH or ER stress machineries as affecting alkylating therapy toxicity. Mol Cancer Ther; 15(12); 3000-14. ©2016 AACR.
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