ArticleJournal of immunology research2023
The SIX1/LDHA Axis Promotes Lactate Accumulation and Leads to NK Cell Dysfunction in Pancreatic Cancer.
Article in Journal of immunology research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 27 citations in OpenAlex.
- Targeting the MICA/B-NKG2D axis in cancer: from molecular structure to immunotherapeutic strategies-a narrative review.Translational cancer research · 2026Review
- Article
- Lactate-mediated NK cell dysfunction as a prognostic marker and therapeutic target in breast cancer.Cell death discovery · 2026Article
- Association Between Lactate and ICU-Acquired Infection in Critically Ill Patients With Sepsis: A Retrospective Study Using the MIMIC-IV Database.Journal of cellular and molecular medicine · 2026Article
- Research progress on immune tolerance mechanisms in liver metastatic tumors and the "Liver-metastasis-oriented shared-mechanism therapeutic strategy" approach.Medical review (2021) · 2026Review
- Tumor-immune metabolic tug-of-war: from immune escape to targeting metabolic rewiring in cancer therapy.Frontiers in cell and developmental biology · 2026Review
- Extracellular Metabolites and Natural Killer Cell Antitumor Function: Mechanisms and Therapeutic Strategies.Research (Washington, D.C.) · 2026Review
- Lactylation modification in lung cancer: A review of current research and future directions (Review).Oncology reports · 2025Review
- Lactylation modifications in urological diseases: molecular mechanisms and biological implications.Clinical epigenetics · 2025Review
- Decoding the metabolic dialogue in the tumor microenvironment: from immune suppression to precision cancer therapies.Experimental hematology & oncology · 2025Review
- Identification of LDHA as a Potential Therapeutic Target for Pulmonary Hypertension Through Modulation of Endothelial-To-Mesenchymal Transition.Journal of cellular and molecular medicine · 2025Article
- Burning lactic acid: a road to revitalizing antitumor immunity.Frontiers of medicine · 2025Review
- Review
- Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review).Molecular medicine reports · 2025Review
- Sine oculis homeobox homolog family function in gastrointestinal cancer: Progression and comprehensive analysis.World journal of clinical oncology · 2025Review
- Tumor metabolic regulators: key drivers of metabolic reprogramming and the promising targets in cancer therapy.Molecular cancer · 2025Review
- Pain, lactate, and anesthetics: intertwined regulators of tumor metabolism and immunity.Frontiers in oncology · 2025Review
- Emerging mechanisms and promising approaches in pancreatic cancer metabolism.Cell death & disease · 2024Review
- A lactate-responsive gene signature predicts the prognosis and immunotherapeutic response of patients with triple-negative breast cancer.Cancer innovation · 2024Article
- Transcriptional regulation and post-translational modifications in the glycolytic pathway for targeted cancer therapy.Acta pharmacologica Sinica · 2024Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Background: Pancreatic cancer (PC) is a malignant cancer with poor prognosis and high mortality rate. Sine oculis homeobox homolog 1 (SIX1) participates in the development of many cancers. However, the function of SIX1 in PC is not fully understood. Methods: SIX1 expression was determined using immunohistochemistry in PC tissues and cell lines. Glucose consumption, lactate production, and ATP assays were used to detect the function of SIX1. PC cells and NK cells were cocultured to study the effect of SIX1 overexpression in PC cells on NK cell function. Chromatin immunoprecipitation (ChIP) assays were used to study the relationship between SIX1 and lactate dehydrogenase A (LDHA). A series of in vitro and in vivo assays were further applied to elucidate the important role of the SIX1/LDHA axis in metabolism and NK cell dysfunction in PC. Results: SIX1 was significantly upregulated in PC tissue; SIX1 overexpression promoted the glycolysis capacity of PANC-1 and CFPAC-1 cells and resulted in NK cell dysfunction after the NK cells had been cultured with PC cells. LDHA inhibitor partially restored the promotion of PC caused by SIX1 overexpression. According to ChIP assays, SIX1 directly binds to the LDHA promoter region. Moreover, LDHA inhibitor and lactate transporter blocker treatment promoted the function of NK cells cocultured with PC cells. In vivo experiments yielded the same results. Conclusion: The SIX1/LDHA axis promotes lactate accumulation and leads to NK cell dysfunction in PC.
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