ArticleCarcinogenesis2016
TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3.
Article in Carcinogenesis, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 105 citations in OpenAlex.
- Conversational Artificial Intelligence-Enabled Precision Oncology Reveals Context-Specific TGFβ and JAK/STAT Alterations in Pancreatic Cancer.medRxiv : the preprint server for health sciences · 2026Article
- Oxaliplatin upregulates Cyr61 expression by inhibiting the Hippo-YAP pathway which contributes to drug resistance of colorectal cancer cells.Discover oncology · 2026Article
- Current Advances in Preclinical Patient-Derived Cultivation Models for Individualized Drug Response Prediction in Pancreatic Cancer.Oncology research · 2026Review
- BH3 mimetic and dual PI3K/mTOR inhibitor attenuates gemcitabine resistance in triple-negative breast cancer.Medical oncology (Northwood, London, England) · 2025Article
- Fibrotic Fortresses and Therapeutic Frontiers: Pancreatic Stellate Cells and the Extracellular Matrix in Pancreatic Cancer.Cancer medicine · 2025Review
- The multi-faceted roles of cancer-associated fibroblasts in pancreatic cancer.Cellular signalling · 2025Review
- Current Organoid Culture Systems in Pancreatic Cancer.Current topics in medicinal chemistry · 2025Review
- EZH2 deletion does not affect acinar regeneration but restricts progression to pancreatic cancer in mice.JCI insight · 2024Article
- The Crosstalk Analysis between mPSCs and Panc1 Cells Identifies CCN1 as a Positive Regulator of Gemcitabine Sensitivity in Pancreatic Cancer Cells.International journal of molecular sciences · 2024Article
- Elucidation of the Gemcitabine Transporters ofInternational journal of molecular sciences · 2024Article
- Review
- Chemotherapy-initiated cysteine-rich protein 61 decreases acute B-lymphoblastic leukemia chemosensitivity.Journal of cancer research and clinical oncology · 2024Article
- Macrophages reprogramming driven by cancer-associated fibroblasts under FOLFIRINOX treatment correlates with shorter survival in pancreatic cancer.Cell communication and signaling : CCS · 2024Article
- Hypoxia-initiated Cysteine-rich protein 61 secretion promotes chemoresistance of acute B lymphoblastic leukemia cells.American journal of cancer research · 2024Article
- A stumbling block in pancreatic cancer treatment: drug resistance signaling networks.Frontiers in cell and developmental biology · 2024Review
- Deletion of the mRNA stability factorNAR cancer · 2023Article
- Barriers and opportunities for gemcitabine in pancreatic cancer therapy.American journal of physiology. Cell physiology · 2023Review
- Pancreatic stellate cell-induced gemcitabine resistance in pancreatic cancer is associated with LDHA- and MCT4-mediated enhanced glycolysis.Cancer cell international · 2023Article
- Nucleoside transporters and immunosuppressive adenosine signaling in the tumor microenvironment: Potential therapeutic opportunities.Pharmacology & therapeutics · 2022Review
- Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer in part due to inherent resistance to chemotherapy, including the first-line drug gemcitabine. Although low expression of the nucleoside transporters hENT1 and hCNT3 that mediate cellular uptake of gemcitabine has been linked to gemcitabine resistance, the mechanisms regulating their expression in the PDAC tumor microenvironment are largely unknown. Here, we report that the matricellular protein cysteine-rich angiogenic inducer 61 (CYR61) negatively regulates the nucleoside transporters hENT1 and hCNT3. CRISPR/Cas9-mediated knockout of CYR61 increased expression of hENT1 and hCNT3, increased cellular uptake of gemcitabine and sensitized PDAC cells to gemcitabine-induced apoptosis. In PDAC patient samples, expression of hENT1 and hCNT3 negatively correlates with expression of CYR61 . We demonstrate that stromal pancreatic stellate cells (PSCs) are a source of CYR61 within the PDAC tumor microenvironment. Transforming growth factor-β (TGF-β) induces the expression of CYR61 in PSCs through canonical TGF-β-ALK5-Smad2/3 signaling. Activation of TGF-β signaling or expression of CYR61 in PSCs promotes resistance to gemcitabine in PDAC cells in an in vitro co-culture assay. Our results identify CYR61 as a TGF-β-induced stromal-derived factor that regulates gemcitabine sensitivity in PDAC and suggest that targeting CYR61 may improve chemotherapy response in PDAC patients.
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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.