ArticleJournal of experimental & clinical cancer research : CR2018
Hypoxia potentiates gemcitabine-induced stemness in pancreatic cancer cells through AKT/Notch1 signaling.
Article in Journal of experimental & clinical cancer research : CR, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 93 citations in OpenAlex.
- MMSDH facilitates ACSL4 propionylation to counteract ferroptosis upon hypoxia and impairs PDAC chemotherapy efficacy.Nature cancer · 2026Article
- The CaThe Journal of biological chemistry · 2026Article
- AMPK-activated BAP1 regulates pVHL stability and tumor-suppressive functions.Cell death and differentiation · 2026Article
- Expanding the payload scope in antibody-drug conjugates by delivery of hydroxy-containing drugs through self-immolative phosphoramidates.Nature communications · 2026Article
- Scoparone induces mitophagy and apoptosis via ROS accumulation in pancreatic cancer cells.Current research in toxicology · 2026Article
- Integrated scRNA-seq and transcriptome analyses uncover the effects of UBE2H on the immune microenvironment regulation in pancreatic cancer.Cancer cell international · 2025Article
- New insights into Notch signaling as a crucial pathway of pancreatic cancer stem cell behavior by chrysin-polylactic acid-based nanocomposite.Discover oncology · 2025Review
- 4'-Demethylpodophyllotoxin functions as a mechanism-driven therapy by targeting the PI3K-AKT pathway in Colorectal cancer.Translational oncology · 2025Article
- The role of notch signaling pathway and non-coding RNAs in cancer and inflammation: progress, therapeutic insights, and future directions.Frontiers in immunology · 2025Review
- The regulatory role of lncRNA in tumor drug resistance: refracting light through a narrow aperture.Oncology research · 2025Review
- Novel insight and perspectives of nanoparticle-mediated gene delivery and immune-modulating therapies for pancreatic cancer.Journal of nanobiotechnology · 2024Review
- Troponin T1 in tumorigenesis and immune modulation: Insights into multiple cancers and kidney renal clear cell carcinoma.Journal of cellular and molecular medicine · 2024Article
- Hypoxia-induced epigenetic regulation of miR-485-3p promotes stemness and chemoresistance in pancreatic ductal adenocarcinoma via SLC7A11-mediated ferroptosis.Cell death discovery · 2024Article
- Novel insights into the roles of migrasome in cancer.Discover oncology · 2024Review
- Gemcitabine Modulates HLA-I Regulation to Improve Tumor Antigen Presentation by Pancreatic Cancer Cells.International journal of molecular sciences · 2024Article
- Improved Antitumor Efficiency ofInternational journal of nanomedicine · 2024Article
- Targeting the SMURF2-HIF1α axis: a new frontier in cancer therapy.Frontiers in oncology · 2024Review
- Post-translational modification of CDK1-STAT3 signaling by fisetin suppresses pancreatic cancer stem cell properties.Cell & bioscience · 2023Article
- HGF/c-Met pathway inhibition combined with chemotherapy increases cytotoxic T-cell infiltration and inhibits pancreatic tumour growth and metastasis.Cancer letters · 2023Article
- Retraction Note: Long non-coding RNA MACC1-AS1 promoted pancreatic carcinoma progression through activation of PAX8/ NOTCH1 signaling pathway.Journal of experimental & clinical cancer research : CR · 2023Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundProfound chemoresistance remains an intractable obstacle in pancreatic cancer treatment. Pancreatic cancer stem cells (CSCs) and the ubiquitous hypoxic niche have been proposed to account for drug resistance. However, the mechanism involved requires further exploration. This study investigated whether the hypoxic niche enhances gemcitabine-induced stemness and acquired resistance in pancreatic cancer cells by activating the AKT/Notch1 signaling cascade. The therapeutic effects of blockading this signaling cascade on gemcitabine-enriched CSCs were also investigated.
methodsThe expression levels of CSC-associated markers Bmi1 and Sox2 as well as those of proteins involved in AKT/Notch1 signaling were measured by Western blot analysis. The expression level of the pancreatic CSC marker CD24 was measured by flow cytometry. Change in gemcitabine sensitivity was evaluated by the MTT assay. The ability of sphere formation was tested by the sphere-forming assay in stem cell medium. The ability of migration and invasion was detected by the transwell migration/invasion assay. A mouse xenograft model of pancreatic cancer was established to determine the effect of Notch1 inhibition on the killing effect of gemcitabine in vivo. The ability of metastasis was investigated by an in vivo lung metastasis assay.
resultsGemcitabine promoted pancreatic cancer cell stemness and associated malignant phenotypes such as enhanced migration, invasion, metastasis, and chemoresistance. The AKT/Notch1 signaling cascade was activated after gemcitabine treatment and mediated this process. Blockading this pathway enhanced the killing effect of gemcitabine in vivo. However, supplementation with hypoxia treatment synergistically enhanced the AKT/Notch1 signaling pathway and collaboratively promoted gemcitabine-induced stemness.
conclusionsThese findings demonstrate a novel mechanism of acquired gemcitabine resistance in pancreatic cancer cells through induction of stemness, which was mediated by the activation of AKT/Notch1 signaling and synergistically aggravated by the ubiquitous hypoxic niche. Our results might provide new insights for identifying potential targets for reversing chemoresistance in patients with pancreatic cancer.
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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.