ArticleAntioxidants (Basel, Switzerland)2023
Monocarboxylate Transporter-1 (MCT1)-Mediated Lactate Uptake Protects Pancreatic Adenocarcinoma Cells from Oxidative Stress during Glutamine Scarcity Thereby Promoting Resistance against Inhibitors of Glutamine Metabolism.
Article in Antioxidants (Basel, Switzerland), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 16 citations in OpenAlex.
- Myelin Dynamics at the Axon-Oligodendrocyte Interface: Adaptive Conduction Homeostasis in Demyelination, Remyelination and White Matter Repair.International journal of molecular sciences · 2026Review
- Stable Isotope-Resolved Metabolomics in Elucidating Mitochondrial Metabolic Reprogramming and Therapeutic Targets.Biomedical chromatography : BMC · 2026Review
- Piezo1 in digestive homeostasis and disease: Barrier function, immune signalling, cellular injury and metabolism.Clinical and translational medicine · 2026Review
- Metabolic plasticity in pancreatic ductal adenocarcinoma progression and response to treatment.Molecular cancer · 2026Review
- A review of soluble mediator and cytokine networks linking combination immunotherapy, tumor microenvironment remodeling and skeletal muscle dysfunction.Frontiers in immunology · 2026Review
- Regulation of Intestinal Butyrate Transporters by Oxidative and Inflammatory Status.Antioxidants (Basel, Switzerland) · 2025Review
- Biomimetic Tumour Model Systems for Pancreatic Ductal Adenocarcinoma in Relation to Photodynamic Therapy.International journal of molecular sciences · 2025Review
- Article
- Article
- Tumor microenvironment-driven resistance to immunotherapy in non-small cell lung cancer: strategies for Cold-to-Hot tumor transformation.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Review
- GLS and GLS2 Glutaminase Isoenzymes in the Antioxidant System of Cancer Cells.Antioxidants (Basel, Switzerland) · 2024Review
- The Role of Nrf2 in the Regulation of Mitochondrial Function and Ferroptosis in Pancreatic Cancer.Antioxidants (Basel, Switzerland) · 2024Review
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Metabolic compartmentalization of stroma-rich tumors, like pancreatic ductal adenocarcinoma (PDAC), greatly contributes to malignancy. This involves cancer cells importing lactate from the microenvironment (reverse Warburg cells) through monocarboxylate transporter-1 (MCT1) along with substantial phenotype alterations. Here, we report that the reverse Warburg phenotype of PDAC cells compensated for the shortage of glutamine as an essential metabolite for redox homeostasis. Thus, oxidative stress caused by glutamine depletion led to an Nrf2-dependent induction of MCT1 expression in pancreatic T3M4 and A818-6 cells. Moreover, greater MCT1 expression was detected in glutamine-scarce regions within tumor tissues from PDAC patients. MCT1-driven lactate uptake supported the neutralization of reactive oxygen species excessively produced under glutamine shortage and the resulting drop in glutathione levels that were restored by the imported lactate. Consequently, PDAC cells showed greater survival and growth under glutamine depletion when utilizing lactate through MCT1. Likewise, the glutamine uptake inhibitor V9302 and glutaminase-1 inhibitor CB839 induced oxidative stress in PDAC cells, along with cell death and cell cycle arrest that were again compensated by MCT1 upregulation and forced lactate uptake. Our findings show a novel mechanism by which PDAC cells adapt their metabolism to glutamine scarcity and by which they develop resistance against anticancer treatments based on glutamine uptake/metabolism inhibition.
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