ArticleMolecular cancer therapeutics2021
EMT-Induced Gemcitabine Resistance in Pancreatic Cancer Involves the Functional Loss of Equilibrative Nucleoside Transporter 1.
Article in Molecular cancer therapeutics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 52 citations in OpenAlex.
- Molecular Subtypes of Pancreatic Cancer: A Review of the Literature.Current issues in molecular biology · 2026Review
- Combining ferroptosis inducers with gemcitabine to enhance treatment efficacy in pancreatic cancer.Cancer & metabolism · 2026Article
- The m6A-circRNA axis: a therapeutic prospect for gastric cancer.Cell biology and toxicology · 2026Review
- Mesoporous Silica Nanoparticles With Customized Drug Ratio/Loading for Effective Treatment of Gemcitabine-Resistant Pancreatic Tumors.Advanced nanobiomed research · 2026Article
- Solute Carrier transporters in tumor metabolism and immune modulation: implications for therapy.Journal of translational medicine · 2026Review
- Role of solute carrier transporters in the biodistribution and toxicity of chemotherapeutic drugs.Pharmacological reviews · 2026Review
- Uridine-Based PET/NIRF Dual-Modality imaging for precision tumor diagnosis and surgery.European journal of nuclear medicine and molecular imaging · 2026Article
- Chemotherapy-Treated Breast Cancer Cells Activate the WNT Signaling Pathway to Enter a Diapause-Like Early Persister State.Cancer research · 2026Article
- Loss of Regulator of G Protein Signaling 11 Promotes Protumorigenic Features in Pancreatic Cancer.Molecular cancer research : MCR · 2026Article
- Epithelial-Mesenchymal Transition Suppression by ML210 Enhances Gemcitabine Anti-Tumor Effects on PDAC Cells.Biomolecules · 2025Article
- Molecular Mechanisms of Gemcitabine Resistance in Cholangiocarcinoma.Oncology research · 2025Review
- Pentagalloyl Glucose fromPharmaceuticals (Basel, Switzerland) · 2024Article
- Clinical and Genomic Features of Classical and Basal Transcriptional Subtypes in Pancreatic Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Unveiling the resistance to therapies in pancreatic ductal adenocarcinoma.Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy · 2024Review
- Growth Hormone Upregulates Melanoma Drug Resistance and Migration via Melanoma-Derived Exosomes.Cancers · 2024Article
- Characterization of Equilibrative Nucleoside Transport of the Pancreatic Cancer Cell Line: Panc-1.Turkish journal of pharmaceutical sciences · 2024Article
- Growth Hormone Receptor Antagonist Markedly Improves Gemcitabine Response in a Mouse Xenograft Model of Human Pancreatic Cancer.International journal of molecular sciences · 2024Article
- Elevated SLC1A5 associated with poor prognosis and therapeutic resistance to transarterial chemoembolization in hepatocellular carcinoma.Journal of translational medicine · 2024Article
- Molecular profile of metastasis, cell plasticity and EMT in pancreatic cancer: a pre-clinical connection to aggressiveness and drug resistance.Cancer metastasis reviews · 2024Review
- Role of Exosomes in Epithelial-Mesenchymal Transition.ACS applied bio materials · 2024Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Epithelial-mesenchymal transition (EMT) in cancer cells drives cancer chemoresistance, yet the molecular events of EMT that underpin the acquisition of chemoresistance are poorly understood. Here, we demonstrate a loss of gemcitabine chemosensitivity facilitated by human equilibrative nucleoside transporter 1 (ENT1) during EMT in pancreatic cancer and identify that cadherin switching from the epithelial (E) to neuronal (N) type, a hallmark of EMT, contributes to this loss. Our findings demonstrate that N-cadherin decreases ENT1 expression, membrane localization, and gemcitabine transport, while E-cadherin augments each of these. Besides E- and N-cadherin, another epithelial cell adhesion molecule, EpCAM, played a more prominent role in determining ENT1 membrane localization. Forced expression of EpCAM opposed cadherin switching with restored ENT1 expression, membrane localization, and gemcitabine transport in EMT-committed pancreatic cancer cells. In gemcitabine-treated mice, EpCAM-positive tumors had high ENT1 expression and reduced metastasis, whereas tumors with N-cadherin expression resisted gemcitabine treatment and formed extensive secondary metastatic nodules. Tissue microarray profiling and multiplexed IHC analysis of pancreatic cancer patient-derived primary tumors revealed EpCAM and ENT1 cell surface coexpression is favored, and ENT1 plasma membrane expression positively predicted median overall survival times in patients treated with adjuvant gemcitabine. Together, our findings identify ENT1 as an inadvertent target of EMT signaling mediated by cadherin switching and provide a mechanism by which mesenchymal pancreatic cancer cells evade gemcitabine therapy during EMT.
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