ArticleOncogene2020
MUC1 oncoprotein mitigates ER stress via CDA-mediated reprogramming of pyrimidine metabolism.
Article in Oncogene, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 49 citations in OpenAlex.
- KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer.Cancer research · 2026Article
- Evolution of the MUC1 gene in eutherian mammals as an adaptation responsible for the increasing incidence of cancer in humans.Biochimica et biophysica acta. Reviews on cancer · 2026Review
- The canonical ER stress IRE1α/XBP1 pathway mediates skeletal muscle wasting during pancreatic cancer cachexia.EMBO molecular medicine · 2025Article
- Tumor-stromal metabolic crosstalk in pancreatic cancer.Trends in cell biology · 2025Review
- Acquired resistance in cancer: towards targeted therapeutic strategies.Nature reviews. Cancer · 2025Review
- Prodelphinidin from purple sweet potato induces apoptosis in human triple-negative breast cancer cells via ROS-mediated ER stress activation.Medical oncology (Northwood, London, England) · 2025Article
- Causal association between metabolites and upper gastrointestinal tumors: A Mendelian randomization study.Molecular medicine reports · 2024Article
- Sea Cucumber Viscera Processed by Protease Hydrolysis Combined withAntioxidants (Basel, Switzerland) · 2024Article
- Article
- The MUC1-HIF-1α signaling axis regulates pancreatic cancer pathogenesis through polyamine metabolism remodeling.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.Nature cell biology · 2024Article
- DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation.bioRxiv : the preprint server for biology · 2024Article
- The multifaceted role of MUC1 in tumor therapy resistance.Clinical and experimental medicine · 2023Review
- Activation of Vitamin D/VDR Signaling Reverses Gemcitabine Resistance of Pancreatic Cancer Cells Through Inhibition of MUC1 Expression.Digestive diseases and sciences · 2023Article
- Nucleotide metabolism: a pan-cancer metabolic dependency.Nature reviews. Cancer · 2023Review
- Mitochondrial Metabolism in Pancreatic Ductal Adenocarcinoma: From Mechanism-Based Perspectives to Therapy.Cancers · 2023Review
- ENT1 blockade by CNX-774 overcomes resistance to DHODH inhibition in pancreatic cancer.Cancer letters · 2023Article
- Pazopanib restricts small cell lung cancer proliferation via reactive oxygen species-mediated endoplasmic reticulum stress.Thoracic cancer · 2022Article
- DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor-resistant lung cancer therapy.Experimental & molecular medicine · 2022Article
- Exploring the metabolic landscape of pancreatic ductal adenocarcinoma cells using genome-scale metabolic modeling.iScience · 2022Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The Mucin 1 (MUC1) protein is overexpressed in various cancers and mediates chemotherapy resistance. However, the mechanism is not fully understood. Given that most chemotherapeutic drugs disrupt ER homeostasis as part of their toxicity, and MUC1 expression is regulated by proteins involved in ER homeostasis, we investigated the link between MUC1 and ER homeostasis. MUC1 knockdown in pancreatic cancer cells enhanced unfolded protein response (UPR) signaling and cell death upon ER stress induction. Transcriptomic analysis revealed alterations in the pyrimidine metabolic pathway and cytidine deaminase (CDA). ChIP and CDA activity assays showed that MUC1 occupied CDA gene promoter upon ER stress induction correlating with increased CDA expression and activity in MUC1-expressing cells as compared with MUC1 knockdown cells. Inhibition of either the CDA or pyrimidine metabolic pathway diminished survival in MUC1-expressing cancer cells upon ER stress induction. Metabolomic analysis demonstrated that MUC1-mediated CDA activity corresponded to deoxycytidine to deoxyuridine metabolic reprogramming upon ER stress induction. The resulting increase in deoxyuridine mitigated ER stress-induced cytotoxicity. In addition, given (1) the established roles of MUC1 in protecting cells against reactive oxygen species (ROS) insults, (2) ER stress-generated ROS further promote ER stress and (3) the emerging anti-oxidant property of deoxyuridine, we further investigated if MUC1 regulated ER stress by a deoxyuridine-mediated modulation of ROS levels. We observed that deoxyuridine could abrogate ROS-induced ER stress to promote cancer cell survival. Taken together, our findings demonstrate a novel MUC1-CDA axis of the adaptive UPR that provides survival advantage upon ER stress induction.
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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.