ArticleCell death & disease2015
Integrated stress response is critical for gemcitabine resistance in pancreatic ductal adenocarcinoma.
Article in Cell death & disease, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
75 citing papers in PubMed, 2 syntheses or guidelines pooled it, 125 citations in OpenAlex.
- Dual roles and therapeutic potential of Keap1-Nrf2 pathway in pancreatic cancer: a systematic review.Cell communication and signaling : CCS · 2019Pooled it
- New Hope for Pancreatic Ductal Adenocarcinoma Treatment Targeting Endoplasmic Reticulum Stress Response: A Systematic Review.International journal of molecular sciences · 2018Pooled it
- Aporphine AlkaloidPharmaceuticals (Basel, Switzerland) · 2026Article
- Unfolded Protein Response Pathways in Cancer: Mechanisms, Tumor Biology and Therapeutic Opportunities.Molecular diagnosis & therapy · 2026Review
- Chidamide induces ROS-driven ZAKα-dependent ribotoxic stress in endometrial cancer and enhances radiosensitivity in vitro and in vivo.Cell death & disease · 2026Article
- Allosteric disordering of eIF2B regulates the integrated stress response.Nature chemical biology · 2026Article
- Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases.Signal transduction and targeted therapy · 2026Review
- NUPR1 as a central stress-adaptation node in cancer: integrating metabolic rewiring, cell death, and therapy resistance.Journal of biomedical science · 2026Review
- Targeting dormant cancer cells: ferroptosis as a precision therapeutic strategy.Cellular & molecular biology letters · 2026Review
- CDX2 confers ferroptosis resistance in stage II-III colon cancer via upregulation of NUPR1.Cell death & disease · 2026Article
- GCN2 in Cancer: Molecular Mechanisms to Therapeutic Potential.Current cancer drug targets · 2026Review
- Targeting the unfolded protein response in cancer: mechanisms, small-molecule inhibitors, and translational challenges.Frontiers in immunology · 2026Review
- Synergistic antitumor activity of sorafenib and the NUPR1 inhibitor LZX-2-73 in multiple cancer models.Cell death & disease · 2025Article
- The Unfolded Protein Response-Novel Mechanisms, Challenges, and Key Considerations for Therapeutic Intervention.Cancers · 2025Review
- Bioactive polymers as stimulus-responsive anti-metastatic combination agents to treat pancreatic cancer.Biomaterials · 2025Article
- Rational development of gemcitabine-based nanoplatform for targeting SERPINB9/Granzyme B axis to overcome chemo-immune-resistance.Nature communications · 2025Article
- Role of C/EBP Homologous Protein (CHOP) and Nupr1 Interaction in Endoplasmic Reticulum Stress-Induced Apoptosis of Lens Epithelial Cells.Molecular biotechnology · 2025Article
- Maximizing ISRIB Potential Requires Addressing Specificity, Long-term Safety, and Disease-specific Considerations.Current medicinal chemistry · 2025Review
- The Integrated Stress Response in Pancreatic Development, Tissue Homeostasis, and Cancer.Gastroenterology · 2024Review
- Gemcitabine-loaded chitosan nanoparticles enhanced apoptotic and ferroptotic response of gemcitabine treatment alone in the pancreatic cancer cells in vitro.Naunyn-Schmiedeberg's archives of pharmacology · 2024Article
15 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with marked chemoresistance and a 5-year survival rate of 7%. The integrated stress response (ISR) is a cytoprotective pathway initiated in response to exposure to various environmental stimuli. We used pancreatic cancer cells (PCCs) that are highly resistant to gemcitabine (Gem) and an orthotopic mouse model to investigate the role of the ISR in Gem chemoresistance. Gem induced eIF2 phosphorylation and downstream transcription factors ATF4 and CHOP in PCCs, and these effects occurred in an eIF2α-S51 phosphorylation-dependent manner as determined using PANC-1 cells, and wild type and S51 mutant mouse embryo fibroblasts. Blocking the ISR pathway in PCCs with the ISR inhibitor ISRIB or siRNA-mediated depletion of ATF4 resulted in enhanced Gem-mediated apoptosis. Polyribosomal profiling revealed that Gem caused repression of global translation and this effect was reversed by ISRIB or by expressing GADD34 to facilitate eIF2 dephosphorylation. Moreover, Gem promoted preferential mRNA translation as determined in a TK-ATF4 5'UTR-Luciferase reporter assay, and this effect was also reversed by ISRIB. RNA-seq analysis revealed that Gem upregulated eIF2 and Nrf2 pathways, and that ISRIB significantly inhibited these pathways. Gem also induced the expression of the antiapoptotic factors Nupr1, BEX2, and Bcl2a1, whereas ISRIB reduced their expression. In an orthotopic tumor model using PANC-1 cells, ISRIB facilitated Gem-mediated increases in PARP cleavage, which occurred in conjunction with decreased tumor size. These findings indicate that Gem chemoresistance is enhanced by activating multiple ISR-dependent pathways, including eIF2, Nrf2, Nupr1, BEX2, and Bcl2A1. It is suggested that targeting the ISR pathway may be an efficient mechanism for enhancing therapeutic responsiveness to Gem in PDAC.
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Registered trials
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.