ArticleJCI insight2019
eIF4A inhibition circumvents uncontrolled DNA replication mediated by 4E-BP1 loss in pancreatic cancer.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 48 citations in OpenAlex.
- Selective mRNA translation determines adaptative mutability of melanoma cells to anti-BRAF/MEK combination therapy.EMBO molecular medicine · 2026Article
- Decoding the Integrated Stress Response of Pancreatic Cancer: Identifying a Serine-dependent Tumor Subset Under Metabolic Relationships With CAFs.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- A autophagy related gene signature to predict the prognosis of pancreatic carcinoma and tumor immune microenvironment evaluation.Scientific reports · 2025Article
- Review
- The Exon Junction Complex component EIF4A3 plays a splicing-linked oncogenic role in pancreatic ductal adenocarcinoma.Cancer gene therapy · 2024Article
- Reprograming immunosuppressive microenvironment by eIF4G1 targeting to eradicate pancreatic ductal adenocarcinoma.Cell reports. Medicine · 2024Article
- Comprehensive pan-cancer analysis reveals CDC6 as a potential immunomodulatory agent and promising therapeutic target in pancreatic cancer.Translational cancer research · 2024Article
- Targeting eIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer.The Journal of clinical investigation · 2023Article
- TORC1 phosphorylates and inhibits the ribosome preservation factor Stm1 to activate dormant ribosomes.The EMBO journal · 2023Article
- High throughput sequencing revealed enhanced cell cycle signaling in SLE patients.Scientific reports · 2023Article
- The Impact of Oxidative Stress and AKT Pathway on Cancer Cell Functions and Its Application to Natural Products.Antioxidants (Basel, Switzerland) · 2022Review
- Action and function of helicases on RNA G-quadruplexes.Methods (San Diego, Calif.) · 2022Review
- Microarray analysis of breast cancer gene expression profiling in response to 2-deoxyglucose, metformin, and glucose starvation.Cancer cell international · 2022Article
- Epithelial X-Box Binding Protein 1 Coordinates Tumor Protein p53-Driven DNA Damage Responses and Suppression of Intestinal Carcinogenesis.Gastroenterology · 2022Article
- Targeted intervention of eIF4A1 inhibits EMT and metastasis of pancreatic cancer cells via c-MYC/miR-9 signaling.Cancer cell international · 2021Article
- Proteomics reveal cap-dependent translation inhibitors remodel the translation machinery and translatome.Cell reports · 2021Article
- Narrative review of emerging roles for AKT-mTOR signaling in cancer radioimmunotherapy.Annals of translational medicine · 2021Review
- Regulation of DNA duplication by the mTOR signaling pathway.Cell cycle (Georgetown, Tex.) · 2021Review
- Repurposing anticancer drugs for the management of COVID-19.European journal of cancer (Oxford, England : 1990) · 2020Review
- KIF23 enhances cell proliferation in pancreatic ductal adenocarcinoma and is a potent therapeutic target.Annals of translational medicine · 2020Article
Corrections and comments
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Authors and funding
18 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) relies on hyperactivated protein synthesis. Consistently, human and mouse PDAC lose expression of the translational repressor and mTOR target 4E-BP1. Using genome-wide polysome profiling, we here explore mRNAs whose translational efficiencies depend on the mTOR/4E-BP1 axis in pancreatic cancer cells. We identified a functional enrichment for mRNAs encoding DNA replication and repair proteins, including RRM2 and CDC6. Consequently, 4E-BP1 depletion favors DNA repair and renders DNA replication insensitive to mTOR inhibitors, in correlation with a sustained protein expression of CDC6 and RRM2, which is inversely correlated with 4E-BP1 expression in PDAC patient samples. DNA damage and pancreatic lesions induced by an experimental pancreatitis model uncover that 4E-BP1/2-deleted mice display an increased acinar cell proliferation and a better recovery than WT animals. Targeting translation, independently of 4E-BP1 status, using eIF4A RNA helicase inhibitors (silvestrol derivatives) selectively modulates translation and limits CDC6 expression and DNA replication, leading to reduced PDAC tumor growth. In summary, 4E-BP1 expression loss during PDAC development induces selective changes in translation of mRNA encoding DNA replication and repair protein. Importantly, targeting protein synthesis by eIF4A inhibitors circumvents PDAC resistance to mTOR inhibition.
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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.