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Research Article Open access CC BY 4.0

Lactic Acid Inhibits the Cytotoxicity of NK-92 Cells via Activating the Lactate Receptor GPR81

Yaobiao Huang, Wenjie Nie, Sudan Ye, Chun Chen

Annual Research & Review in Biology · pp. 1–10 · Published 7 Apr 2023

10.9734/arrb/2023/v38i330573

Abstract

Aims: Lactate acid functions as not only an energy source but a signaling molecule through the lactate receptor GPR81 under physiological conditions. However, the pathological role of lactic acid in the tumor microenvironment remains unclear, particularly for immune cells. Methodology: NK-92 cells were treated with L-lactic acid solutions at final concentrations of 10, 20, 30, and 40 mM, and its cell viability and cytotoxicity on A549 cells and A375 cells were evaluated by CCK8 assay and crystal violet assay, respectively. Furthermore, qPCR was used to assess the expression of GPR81 and cytotoxicity-related genes in NK-92 cells treated with antagonist and agonist. And their relationship between lactate/GPR81 pathway and cytotoxicity-related genes were analyzed by Pearson’s correlation. Results: The viability of NK-92 cells was inhibited by L-lactic acid with increasing concentration. Additionally, the cytotoxic activity against tumor cells of NK-92 cells treated with L-lactic acid decreased with increasing concentration. Moreover, qPCR results demonstrated that GPR81 can be activated by lactic acid or agonist (3,5-DHBA) and downregulate the expression cytotoxicity-related genes which included FASLG gene(Fas Ligand),TNF-α gene(Tumor necrosis factor-α), INFG gene (Interferon-γ), RPF1 gene (Perforin 1), GZMA gene (Granzyme A), GZMB gene (Granzyme B), GZMH gene (Granzyme H), GAMK gene (Granzyme K) and GZMM gene (Granzyme M). And the expression of GPR81 returned to near-control level when treated with L-lactic acid in the presence of antagonist (3-OBA), the expression of cytotoxicity-related genes did as well. Pearson’s correlation analysis of cytotoxicity-related genes with GPR81 revealed that their correlation coefficient seems negative. Conclusion: Lactic acid can activate the GPR81 to downregulate the expression of cytotoxicity-related genes, subsequently lower the cytotoxicity of NK-92 cells.

Lactate acid RT-qPCR cytotoxicity-related genes correlation analysis

References (28)

  1. 1 Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method [DOI]
  2. 2 LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells [DOI]
  3. 3 Inhibitory effect of tumor cell–derived lactic acid on human T cells [DOI]
  4. 4 The Science and Translation of Lactate Shuttle Theory [DOI]
  5. 5 Targeting lactate metabolism for cancer therapeutics [DOI]
  6. 6 Tumor microenvironmental physiology and its implications for radiation oncology [DOI]
  7. 7 Lactate modulation of immune responses in inflammatory versus tumour microenvironments [DOI]
  8. 8 Tumor-Derived Lactate Modifies Antitumor Immune Response: Effect on Myeloid-Derived Suppressor Cells and NK Cells [DOI]
  9. 9 Disrupting proton dynamics and energy metabolism for cancer therapy [DOI]
  10. 10 Lactate/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon [DOI]
  11. 11 An Autocrine Lactate Loop Mediates Insulin-Dependent Inhibition of Lipolysis through GPR81 [DOI]
  12. 12 Immunometabolism and natural killer cell responses [DOI]
  13. 13 Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells [DOI]
  14. 14 Lactate in the Tumor Microenvironment: An Essential Molecule in Cancer Progression and Treatment [DOI]
  15. 15 Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of Liver-Resident NK Cells in Colorectal Liver Metastasis [DOI]
  16. 16 Cell Surface Lactate Receptor GPR81 Is Crucial for Cancer Cell Survival [DOI]
  17. 17 The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment [DOI]
  18. 18 Role of GPR81 in lactate-mediated reduction of adipose lipolysis [DOI]
  19. 19 Lactate fuels the human brain during exercise [DOI]
  20. 20 Discovery and mapping of ten novel G protein-coupled receptor genes [DOI]
  21. 21 T-cells produce acidic niches in lymph nodes to suppress their own effector functions [DOI]
  22. 22 Acidity promotes tumour progression by altering macrophage phenotype in prostate cancer [DOI]
  23. 23 G-protein-coupled receptor 81 promotes a malignant phenotype in breast cancer through angiogenic factor secretion [DOI]
  24. 24 The NK-92 cell line—30 years later: its impact on natural killer cell research and treatment of cancer [DOI]
  25. 25 How immune‐cell fate and function are determined by metabolic pathway choice [DOI]
  26. 26 Targeting Lactate Metabolism by Inhibiting MCT1 or MCT4 Impairs Leukemic Cell Proliferation, Induces Two Different Related Death-Pathways and Increases Chemotherapeutic Sensitivity of Acute Myeloid Leukemia Cells [DOI]
  27. 27 Stimulation of lactate receptor (HCAR1) affects cellular DNA repair capacity [DOI]
  28. 28 Crystal Violet Assay for Determining Viability of Cultured Cells [DOI]

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