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The multiple roles of LDH in cancer

Abstract

High serum lactate dehydrogenase (LDH) levels are typically associated with a poor prognosis in many cancer types. Even the most effective drugs, which have radically improved outcomes in patients with melanoma over the past decade, provide only marginal benefit to those with high serum LDH levels. When viewed separately from the oncological, biochemical, biological and immunological perspectives, serum LDH is often interpreted in very different ways. Oncologists usually see high serum LDH only as a robust biomarker of a poor prognosis, and biochemists are aware of the complexity of the various LDH isoforms and of their key roles in cancer metabolism, whereas LDH is typically considered to be oncogenic and/or immunosuppressive by cancer biologists and immunologists. Integrating these various viewpoints shows that the regulation of the five LDH isoforms, and their enzymatic and non-enzymatic functions is closely related to key oncological processes. In this Review, we highlight that serum LDH is far more than a simple indicator of tumour burden; it is a complex biomarker associated with the activation of several oncogenic signalling pathways as well as with the metabolic activity, invasiveness and immunogenicity of many tumours, and constitutes an extremely attractive target for cancer therapy.

Key points

  • High serum lactate dehydrogenase (LDH) levels are associated with a poor prognosis and a negative therapeutic outcome in most patients with cancer, particularly in those with melanoma.

  • The clinical role of LDH is limited to use as a prognostic serum-based biomarker associated with tumour burden; however, it also has a role in several aspects of oncogenesis.

  • LDH isoenzymes have both direct and indirect roles in many aspects of cancer progression through mechanisms such as metabolic pathway plasticity and tumour cell immune evasion.

  • LDH enzymes orchestrate various hallmarks of cancer and are thus considered highly attractive targets for cancer therapy.

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Fig. 1: Structure and function of human lactate dehydrogenase isoenzymes.
Fig. 2: Glycolysis and lactate fermentation.
Fig. 3: Regulation of LDH expression.

References

  1. Amin, M. B. et al. (eds) AJCC Cancer Staging Manual 8th edn (Springer, 2017).

  2. Keung, E. Z. & Gershenwald, J. E. The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care. Expert. Rev. Anticancer. Ther. 18, 775–784 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Petrelli, F. et al. Prognostic role of lactate dehydrogenase in solid tumors: a systematic review and meta-analysis of 76 studies. Acta Oncol. Stockh. Swed. 54, 961–970 (2015).

    Article  CAS  Google Scholar 

  4. Petrelli, F. et al. Prognostic and predictive role of elevated lactate dehydrogenase in patients with melanoma treated with immunotherapy and BRAF inhibitors: a systematic review and meta-analysis. Melanoma Res. 29, 1–12 (2019).

    Article  PubMed  CAS  Google Scholar 

  5. Markert, C. L., Shaklee, J. B. & Whitt, G. S. Evolution of a gene. Multiple genes for LDH isozymes provide a model of the evolution of gene structure, function and regulation. Science 189, 102–114 (1975).

    Article  PubMed  CAS  Google Scholar 

  6. Gallo, M. et al. Lactic dehydrogenase and cancer: an overview. Front. Biosci. Landmark Ed. 20, 1234–1249 (2015).

    Article  PubMed  CAS  Google Scholar 

  7. Nelson, D. L. & Cox, M. M. Lehninger Principles of Biochemistry 8th edn Ch. 15 (Macmillan, 2021).

  8. Forkasiewicz, A. et al. The usefulness of lactate dehydrogenase measurements in current oncological practice. Cell. Mol. Biol. Lett. 25, 35 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Blanco, A. & Zinkham, W. H. Lactate dehydrogenases in human testes. Science 139, 601–602 (1963).

    Article  PubMed  CAS  Google Scholar 

  10. Gonyou, H. W. Behavioral methods to answer questions about sheep. J. Anim. Sci. 69, 4155–4160 (1991).

    Article  PubMed  CAS  Google Scholar 

  11. Goldberg, E. Immunochemical specificity of lactate dehydrogenase-X. Proc. Natl Acad. Sci. USA 68, 349–352 (1971).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Goldberg, E., Eddy, E. M., Duan, C. & Odet, F. LDHC: the ultimate testis-specific gene. J. Androl. 31, 86–94 (2010).

    Article  PubMed  CAS  Google Scholar 

  13. Makkonen, M. Myometrial energy metabolism during pregnancy and normal and dysfunctional labor. Acta Obstet. Gynecol. Scand. Suppl. 71, 1–68 (1977).

    PubMed  CAS  Google Scholar 

  14. Schumann, G. & Klauke, R. New IFCC reference procedures for the determination of catalytic activity concentrations of five enzymes in serum: preliminary upper reference limits obtained in hospitalized subjects. Clin. Chim. Acta 327, 69–79 (2003).

    Article  PubMed  CAS  Google Scholar 

  15. Roman, W. Quantitative estimation of lactate dehydrogenase isoenzymes in serum. I. Review of methods and distribution in human tissues. Enzymologia 36, 189–219 (1969).

    PubMed  CAS  Google Scholar 

  16. Khan, A. A., Allemailem, K. S., Alhumaydhi, F. A., Gowder, S. J. T. & Rahmani, A. H. The biochemical and clinical perspectives of lactate dehydrogenase: an enzyme of active metabolism. Endocr. Metab. Immune Disord. Drug. Targets 20, 855–868 (2020).

    Article  PubMed  CAS  Google Scholar 

  17. Bais, R. & Philcox, M. Approved recommendation on IFCC methods for the measurement of catalytic concentration of enzymes. Part 8. IFCC method for lactate dehydrogenase (l-lactate: NAD+ oxidoreductase, EC 1.1.1.27). International Federation of Clinical Chemistry (IFCC). Eur. J. Clin. Chem. Clin. Biochem. 32, 639–655 (1994).

    PubMed  CAS  Google Scholar 

  18. Amador, E., Dorfman, L. E. & Wacker, W. E. Serum lactic dehydrogenase activity: an analytical assessment of current assays. Clin. Chem. 12, 391–399 (1963).

    Article  PubMed  CAS  Google Scholar 

  19. Erickson, R. J. & Morales, D. R. Clinical use of lactic dehydrogenase. N. Engl. J. Med. 265, 531–534 (1961).

    Article  PubMed  CAS  Google Scholar 

  20. Sharma, P. R., Jain, S., Bamezai, R. N. K. & Tiwari, P. K. Utility of serum LDH isoforms in the assessment of mycobacterium tuberculosis induced pathology in TB patients of Sahariya tribe. Indian J. Clin. Biochem. 25, 57–63 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Agarwala, S. S. et al. LDH correlation with survival in advanced melanoma from two large, randomised trials (Oblimersen GM301 and EORTC 18951). Eur. J. Cancer Oxf. Engl. 45, 1807–1814 (2009).

    Article  Google Scholar 

  22. von Eyben, F. E. A systematic review of lactate dehydrogenase isoenzyme 1 and germ cell tumors. Clin. Biochem. 34, 441–454 (2001).

    Article  Google Scholar 

  23. von Eyben, F. E. et al. Serum lactate dehydrogenase isoenzyme 1 and prediction of death in patients with metastatic testicular germ cell tumors. Clin. Chem. Lab. Med. 39, 38–44 (2001).

    Article  Google Scholar 

  24. Bouafia, F. et al. Profiles and prognostic values of serum LDH isoenzymes in patients with haematopoietic malignancies. Bull. Cancer 91, E229–E240 (2004).

    PubMed  Google Scholar 

  25. Ho, J. et al. Importance of glycolysis and oxidative phosphorylation in advanced melanoma. Mol. Cancer 11, 76 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Khurana, P., Tyagi, N., Salahuddin, A. & Tyagi, S. P. Serum lactate dehydrogenase isoenzymes in breast tumours. Indian. J. Pathol. Microbiol. 33, 355–359 (1990).

    PubMed  CAS  Google Scholar 

  27. Bar, J. et al. Correlation of lactate dehydrogenase isoenzyme profile with outcome in patients with advanced colorectal cancer treated with chemotherapy and bevacizumab or cediranib: retrospective analysis of the HORIZON I study. Clin. Colorectal Cancer 13, 46–53 (2014).

    Article  PubMed  CAS  Google Scholar 

  28. Stubbs, M. & Griffiths, J. R. The altered metabolism of tumors: HIF-1 and its role in the Warburg effect. Adv. Enzym. Regul. 50, 44–55 (2010).

    Article  Google Scholar 

  29. Peppicelli, S., Andreucci, E., Ruzzolini, J., Bianchini, F. & Calorini, L. FDG uptake in cancer: a continuing debate. Theranostics 10, 2944–2948 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  30. He, T.-L. et al. The c-Myc-LDHA axis positively regulates aerobic glycolysis and promotes tumor progression in pancreatic cancer. Med. Oncol. 32, 187 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Shim, H. et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc. Natl Acad. Sci. USA 94, 6658–6663 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Nagao, A., Kobayashi, M., Koyasu, S., Chow, C. C. T. & Harada, H. HIF-1-dependent reprogramming of glucose metabolic pathway of cancer cells and its therapeutic significance. Int. J. Mol. Sci. 20, 238 (2019).

    Article  PubMed Central  Google Scholar 

  33. Kolev, Y., Uetake, H., Takagi, Y. & Sugihara, K. Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1α) pathway, angiogenic factors production and poor prognosis. Ann. Surg. Oncol. 15, 2336–2344 (2008).

    Article  PubMed  Google Scholar 

  34. Cui, J. et al. FOXM1 promotes the Warburg effect and pancreatic cancer progression via transactivation of LDHA expression. Clin. Cancer Res. 20, 2595–2606 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Jiang, W., Zhou, F., Li, N., Li, Q. & Wang, L. FOXM1-LDHA signaling promoted gastric cancer glycolytic phenotype and progression. Int. J. Clin. Exp. Pathol. 8, 6756–6763 (2015).

    PubMed  PubMed Central  Google Scholar 

  36. Shi, M. et al. A novel KLF4/LDHA signaling pathway regulates aerobic glycolysis in and progression of pancreatic cancer. Clin. Cancer Res. 20, 4370–4380 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Fu, D. et al. HMGB2 is associated with malignancy and regulates Warburg effect by targeting LDHB and FBP1 in breast cancer. Cell Commun. Signal. 16, 8 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zha, X. et al. Lactate dehydrogenase B is critical for hyperactive mTOR-mediated tumorigenesis. Cancer Res. 71, 13–18 (2011).

    Article  PubMed  CAS  Google Scholar 

  39. Cui, J. et al. Suppressed expression of LDHB promotes pancreatic cancer progression via inducing glycolytic phenotype. Med. Oncol. 32, 143 (2015).

    Article  PubMed  Google Scholar 

  40. Leiblich, A. et al. Lactate dehydrogenase-B is silenced by promoter hypermethylation in human prostate cancer. Oncogene 25, 2953–2960 (2006).

    Article  PubMed  CAS  Google Scholar 

  41. Liu, J. et al. Aberrant FGFR tyrosine kinase signaling enhances the Warburg effect by reprogramming LDH isoform expression and activity in prostate cancer. Cancer Res. 78, 4459–4470 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Hu, S. et al. miR-200b is a key regulator of tumor progression and metabolism targeting lactate dehydrogenase A in human malignant glioma. Oncotarget 7, 48423–48431 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Zheng, X.-M., Xu, C.-W. & Wang, F. MiR-33b inhibits osteosarcoma cell proliferation through suppression of glycolysis by targeting lactate dehydrogenase A (LDHA). Cell. Mol. Biol. 64, 31–35 (2018).

    Article  PubMed  CAS  Google Scholar 

  44. Li, H. et al. MiR-34b-3 and miR-449a inhibit malignant progression of nasopharyngeal carcinoma by targeting lactate dehydrogenase A. Oncotarget 7, 54838–54851 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Li, L. et al. miR-30a-5p suppresses breast tumor growth and metastasis through inhibition of LDHA-mediated Warburg effect. Cancer Lett. 400, 89–98 (2017).

    Article  PubMed  CAS  Google Scholar 

  46. Xiao, X. et al. The miR-34a-LDHA axis regulates glucose metabolism and tumor growth in breast cancer. Sci. Rep. 6, 21735 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Wang, J. et al. Lactate dehydrogenase A negatively regulated by miRNAs promotes aerobic glycolysis and is increased in colorectal cancer. Oncotarget 6, 19456–19468 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Isozaki, Y. et al. Identification of novel molecular targets regulated by tumor suppressive miR-375 induced by histone acetylation in esophageal squamous cell carcinoma. Int. J. Oncol. 41, 985–994 (2012).

    Article  PubMed  CAS  Google Scholar 

  49. Zhao, D. et al. Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer. Cancer Cell 23, 464–476 (2013).

    Article  PubMed  CAS  Google Scholar 

  50. Jin, L. et al. Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis. Oncogene 36, 3797–3806 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Fan, J. et al. Tyrosine phosphorylation of lactate dehydrogenase A is important for NADH/NAD(+) redox homeostasis in cancer cells. Mol. Cell. Biol. 31, 4938–4950 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Shi, L. et al. SIRT5-mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer. Mol. Oncol. 13, 358–375 (2019).

    Article  PubMed  CAS  Google Scholar 

  53. Cheng, A. et al. Aurora-A mediated phosphorylation of LDHB promotes glycolysis and tumor progression by relieving the substrate-inhibition effect. Nat. Commun. 10, 5566 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Hou, X.-M., Yuan, S.-Q., Zhao, D., Liu, X.-J. & Wu, X.-A. LDH-A promotes malignant behavior via activation of epithelial-to-mesenchymal transition in lung adenocarcinoma. Biosci. Rep. 39, BSR20181476 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Zhao, J. et al. LDHA promotes tumor metastasis by facilitating epithelial‑mesenchymal transition in renal cell carcinoma. Mol. Med. Rep. 16, 8335–8344 (2017).

    Article  PubMed  CAS  Google Scholar 

  56. Giatromanolaki, A. et al. Lactate dehydrogenase 5 (LDH-5) expression in endometrial cancer relates to the activated VEGF/VEGFR2(KDR) pathway and prognosis. Gynecol. Oncol. 103, 912–918 (2006).

    Article  PubMed  CAS  Google Scholar 

  57. Rizwan, A. et al. Relationships between LDH-A, lactate, and metastases in 4T1 breast tumors. Clin. Cancer Res. 19, 5158–5169 (2013).

    Article  PubMed  CAS  Google Scholar 

  58. Wang, H. et al. TOP1MT deficiency promotes GC invasion and migration via the enhancements of LDHA expression and aerobic glycolysis. Endocr. Relat. Cancer 24, 565–578 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Zhu, W. et al. The molecular mechanism and clinical significance of LDHA in HER2-mediated progression of gastric cancer. Am. J. Transl. Res. 10, 2055–2067 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  60. Kim, E.-Y. et al. A novel lactate dehydrogenase inhibitor, 1-(phenylseleno)-4-(trifluoromethyl) benzene, suppresses tumor growth through apoptotic cell death. Sci. Rep. 9, 3969 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Le, A. et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl Acad. Sci. USA 107, 2037–2042 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Sheng, S. L. et al. Knockdown of lactate dehydrogenase A suppresses tumor growth and metastasis of human hepatocellular carcinoma. FEBS J. 279, 3898–3910 (2012).

    Article  PubMed  CAS  Google Scholar 

  63. Xie, H. et al. Targeting lactate dehydrogenase-A inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metab. 19, 795–809 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Flores, A. et al. Increased lactate dehydrogenase activity is dispensable in squamous carcinoma cells of origin. Nat. Commun. 10, 91 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Pretsch, W., Merkle, S., Favor, J. & Werner, T. A mutation affecting the lactate dehydrogenase locus Ldh-1 in the mouse. II. Mechanism of the LDH-A deficiency associated with hemolytic anemia. Genetics 135, 161–170 (1993).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Nilsson, L. M. et al. Mouse genetics suggests cell-context dependency for Myc-regulated metabolic enzymes during tumorigenesis. PLoS Genet. 8, e1002573 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Pathria, G. et al. Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival. EMBO J. 37, e99735 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  68. McCleland, M. L. et al. An integrated genomic screen identifies LDHB as an essential gene for triple-negative breast cancer. Cancer Res. 72, 5812–5823 (2012).

    Article  PubMed  CAS  Google Scholar 

  69. Brisson, L. et al. Lactate dehydrogenase B controls lysosome activity and autophagy in cancer. Cancer Cell 30, 418–431 (2016).

    Article  PubMed  CAS  Google Scholar 

  70. McCleland, M. L. et al. Lactate dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas. Clin. Cancer Res. 19, 773–784 (2013).

    Article  PubMed  CAS  Google Scholar 

  71. Mack, N., Mazzio, E. A., Bauer, D., Flores-Rozas, H. & Soliman, K. F. A. Stable shRNA silencing of lactate dehydrogenase A (LDHA) in human MDA-MB-231 breast cancer cells fails to alter lactic acid production, glycolytic activity, ATP or survival. Anticancer. Res. 37, 1205–1212 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Vanderlinde, R. E. Measurement of total lactate dehydrogenase activity. Ann. Clin. Lab. Sci. 15, 13–31 (1985).

    PubMed  CAS  Google Scholar 

  73. Vesell, E. S. Lactate dehydrogenase Isozymes: substrate inhibition in various human tissues. Science 150, 1590–1593 (1965).

    Article  PubMed  CAS  Google Scholar 

  74. Ždralević, M. et al. Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism. J. Biol. Chem. 293, 15947–15961 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Ratnikov, B. I., Scott, D. A., Osterman, A. L., Smith, J. W. & Ronai, Z. A. Metabolic rewiring in melanoma. Oncogene 36, 147–157 (2017).

    Article  PubMed  CAS  Google Scholar 

  76. Garcia, C. K., Goldstein, J. L., Pathak, R. K., Anderson, R. G. & Brown, M. S. Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle. Cell 76, 865–873 (1994).

    Article  PubMed  CAS  Google Scholar 

  77. Le Floch, R. et al. CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors. Proc. Natl Acad. Sci. USA 108, 16663–16668 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Dhup, S., Dadhich, R. K., Porporato, P. E. & Sonveaux, P. Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr. Pharm. Des. 18, 1319–1330 (2012).

    Article  PubMed  CAS  Google Scholar 

  79. Walenta, S. et al. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 60, 916–921 (2000).

    PubMed  CAS  Google Scholar 

  80. Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).

    Article  PubMed  CAS  Google Scholar 

  81. Fischer, K. et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812–3819 (2007).

    Article  PubMed  CAS  Google Scholar 

  82. Mendler, A. N. et al. Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. Int. J. Cancer 131, 633–640 (2012).

    Article  PubMed  CAS  Google Scholar 

  83. Roth, S., Gmünder, H. & Dröge, W. Regulation of intracellular glutathione levels and lymphocyte functions by lactate. Cell. Immunol. 136, 95–104 (1991).

    Article  PubMed  CAS  Google Scholar 

  84. Haas, R. et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol. 13, e1002202 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Chen, P. et al. Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis. Proc. Natl Acad. Sci. USA 114, 580–585 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Seth, P. et al. Deletion of lactate dehydrogenase-A in myeloid cells triggers antitumor immunity. Cancer Res. 77, 3632–3643 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Morrot, A. et al. Metabolic symbiosis and immunomodulation: how tumor cell-derived lactate may disturb innate and adaptive immune responses. Front. Oncol. 8, 81 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Angelin, A. et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 25, 1282–1293.e7 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Kumagai, S. et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell https://doi.org/10.1016/j.ccell.2022.01.001 (2022).

    Article  PubMed  Google Scholar 

  91. Augoff, K., Hryniewicz-Jankowska, A. & Tabola, R. Lactate dehydrogenase 5: an old friend and a new hope in the war on cancer. Cancer Lett. 358, 1–7 (2015).

    Article  PubMed  CAS  Google Scholar 

  92. García, R. et al. Serum lactate dehydrogenase level as a prognostic factor in Hodgkin’s disease. Br. J. Cancer 68, 1227–1231 (1993).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Schneider, R. J. et al. Prognostic significance of serum lactate dehydrogenase in malignant lymphoma. Cancer 46, 139–143 (1980).

    Article  PubMed  CAS  Google Scholar 

  94. Zhang, X. et al. Prognostic significance of serum LDH in small cell lung cancer: a systematic review with meta-analysis. Cancer Biomark. 16, 415–423 (2016).

    Article  PubMed  CAS  Google Scholar 

  95. Faloppi, L. et al. The role of LDH serum levels in predicting global outcome in HCC patients treated with sorafenib: implications for clinical management. BMC Cancer 14, 110 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Scartozzi, M. et al. The role of LDH serum levels in predicting global outcome in HCC patients undergoing TACE: implications for clinical management. PLoS ONE 7, e32653 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Tas, F. et al. Serum levels of LDH, CEA, and CA19-9 have prognostic roles on survival in patients with metastatic pancreatic cancer receiving gemcitabine-based chemotherapy. Cancer Chemother. Pharmacol. 73, 1163–1171 (2014).

    Article  PubMed  CAS  Google Scholar 

  98. Zhang, Z. et al. Pretreatment lactate dehydrogenase may predict outcome of advanced non small-cell lung cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Cancer Med. 8, 1467–1473 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Armstrong, A. J., George, D. J. & Halabi, S. Serum lactate dehydrogenase predicts for overall survival benefit in patients with metastatic renal cell carcinoma treated with inhibition of mammalian target of rapamycin. J. Clin. Oncol. 30, 3402–3407 (2012).

    Article  PubMed  CAS  Google Scholar 

  100. Jia, Z. et al. An explorative analysis of the prognostic value of lactate dehydrogenase for survival and the chemotherapeutic response in patients with advanced triple-negative breast cancer. Oncotarget 9, 10714–10722 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Pelizzari, G. et al. Lactate dehydrogenase (LDH) response to first-line treatment predicts survival in metastatic breast cancer: first clues for a cost-effective and dynamic biomarker. Cancers 11, 1243 (2019).

    Article  PubMed Central  CAS  Google Scholar 

  102. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).

    Article  PubMed  CAS  Google Scholar 

  104. Robert, C. et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N. Engl. J. Med. 381, 626–636 (2019).

    Article  PubMed  CAS  Google Scholar 

  105. Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 20, 1239–1251 (2019).

    Article  PubMed  CAS  Google Scholar 

  106. Wolchok, J. D. et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J. Clin. Oncol. 40, 127–137 (2022).

    Article  PubMed  CAS  Google Scholar 

  107. Diem, S. et al. Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma. Br. J. Cancer 114, 256–261 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Larkin, J. et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa1910836 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Rosner, S. et al. Peripheral blood clinical laboratory variables associated with outcomes following combination nivolumab and ipilimumab immunotherapy in melanoma. Cancer Med. 7, 690–697 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Dall’Olio, F. G. et al. Tumour burden and efficacy of immune-checkpoint inhibitors. Nat. Rev. Clin. Oncol. 19, 75–90 (2022).

    Article  PubMed  Google Scholar 

  111. Cairo, M. S. & Bishop, M. Tumour lysis syndrome: new therapeutic strategies and classification. Br. J. Haematol. 127, 3–11 (2004).

    Article  PubMed  Google Scholar 

  112. Dercle, L. et al. Rapid and objective CT scan prognostic scoring identifies metastatic patients with long-term clinical benefit on anti-PD-1/-L1 therapy. Eur. J. Cancer 65, 33–42 (2016).

    Article  PubMed  Google Scholar 

  113. Hermes, A., Gatzemeier, U., Waschki, B. & Reck, M. Lactate dehydrogenase as prognostic factor in limited and extensive disease stage small cell lung cancer–a retrospective single institution analysis. Respir. Med. 104, 1937–1942 (2010).

    Article  PubMed  Google Scholar 

  114. Ranasinghe, L. et al. Relationship between serum markers and volume of liver metastases in castration-resistant prostate cancer. Cancer Treat. Res. Commun. 20, 100151 (2019).

    Article  PubMed  Google Scholar 

  115. Kotoh, K. et al. Lactate dehydrogenase production in hepatocytes is increased at an early stage of acute liver failure. Exp. Ther. Med. 2, 195–199 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Kanno, T. et al. Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy. Clin. Chim. Acta 173, 89–98 (1988).

    Article  PubMed  CAS  Google Scholar 

  117. Maekawa, M., Sudo, K., Kanno, T. & Li, S. S. Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency. Biochem. Biophys. Res. Commun. 168, 677–682 (1990).

    Article  PubMed  CAS  Google Scholar 

  118. Shi, Y. & Pinto, B. M. Human lactate dehydrogenase A inhibitors: a molecular dynamics investigation. PLoS ONE 9, e86365 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Rai, G. et al. Discovery and optimization of potent, cell-active pyrazole-based inhibitors of lactate dehydrogenase (LDH). J. Med. Chem. 60, 9184–9204 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Jafary, F., Ganjalikhany, M. R., Moradi, A., Hemati, M. & Jafari, S. Novel peptide inhibitors for lactate dehydrogenase A (LDHA): a survey to inhibit LDHA activity via disruption of protein-protein interaction. Sci. Rep. 9, 4686 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Shelley, M. D. et al. Stereo-specific cytotoxic effects of gossypol enantiomers and gossypolone in tumour cell lines. Cancer Lett. 135, 171–180 (1999).

    Article  PubMed  CAS  Google Scholar 

  122. Zhang, M. et al. Molecular mechanism of gossypol-induced cell growth inhibition and cell death of HT-29 human colon carcinoma cells. Biochem. Pharmacol. 66, 93–103 (2003).

    Article  PubMed  CAS  Google Scholar 

  123. Flack, M. R. et al. Oral gossypol in the treatment of metastatic adrenal cancer. J. Clin. Endocrinol. Metab. 76, 1019–1024 (1993).

    PubMed  CAS  Google Scholar 

  124. Bushunow, P. et al. Gossypol treatment of recurrent adult malignant gliomas. J. Neurooncol. 43, 79–86 (1999).

    Article  PubMed  CAS  Google Scholar 

  125. Van Poznak, C. et al. Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial. Breast Cancer Res. Treat. 66, 239–248 (2001).

    Article  PubMed  Google Scholar 

  126. Manerba, M. et al. Lactate dehydrogenase inhibitors sensitize lymphoma cells to cisplatin without enhancing the drug effects on immortalized normal lymphocytes. Eur. J. Pharm. Sci. 74, 95–102 (2015).

    Article  PubMed  CAS  Google Scholar 

  127. Valvona, C. J. & Fillmore, H. L. Oxamate, but not selective targeting of LDH-A, inhibits medulloblastoma cell glycolysis, growth and motility. Brain Sci. 8, 56 (2018).

    Article  PubMed Central  Google Scholar 

  128. Zhou, M. et al. Warburg effect in chemosensitivity: targeting lactate dehydrogenase-A re-sensitizes taxol-resistant cancer cells to taxol. Mol. Cancer 9, 33 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Zhao, Y. et al. Overcoming trastuzumab resistance in breast cancer by targeting dysregulated glucose metabolism. Cancer Res. 71, 4585–4597 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Qiao, T. et al. Inhibition of LDH-A by oxamate enhances the efficacy of anti-PD-1 treatment in an NSCLC humanized mouse model. Front. Oncol. 11, 632364 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Xiang, J., Zhou, L., He, Y. & Wu, S. LDH-A inhibitors as remedies to enhance the anticancer effects of PARP inhibitors in ovarian cancer cells. Aging 13, 25920–25930 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Cheng, C. S. et al. Functional inhibition of lactate dehydrogenase suppresses pancreatic adenocarcinoma progression. Clin. Transl. Med. 11, e467 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Lea, M. A., Guzman, Y. & Desbordes, C. Inhibition of growth by combined treatment with inhibitors of lactate dehydrogenase and either phenformin or inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3. Anticancer. Res. 36, 1479–1488 (2016).

    PubMed  CAS  Google Scholar 

  134. Yeung, C. et al. Targeting glycolysis through inhibition of lactate dehydrogenase impairs tumor growth in preclinical models of Ewing sarcoma. Cancer Res. 79, 5060–5073 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Oshima, N. et al. Dynamic imaging of LDH inhibition in tumors reveals rapid in vivo metabolic rewiring and vulnerability to combination therapy. Cell Rep. 30, 1798–1810.e4 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Boudreau, A. et al. Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition. Nat. Chem. Biol. 12, 779–786 (2016).

    Article  PubMed  CAS  Google Scholar 

  137. Maftouh, M. et al. Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia. Br. J. Cancer 110, 172–182 (2014).

    Article  PubMed  CAS  Google Scholar 

  138. Li Petri, G. et al. Impact of hypoxia on chemoresistance of mesothelioma mediated by the proton-coupled folate transporter, and preclinical activity of new anti-LDH-A compounds. Br. J. Cancer 123, 644–656 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. El Hassouni, B. et al. Lactate dehydrogenase A inhibition by small molecular entities: steps in the right direction. Oncoscience 7, 76–80 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Manerba, M. et al. Galloflavin (CAS 568-80-9): a novel inhibitor of lactate dehydrogenase. ChemMedChem 7, 311–317 (2012).

    Article  PubMed  CAS  Google Scholar 

  141. Manerba, M. et al. LDH inhibition impacts on heat shock response and induces senescence of hepatocellular carcinoma cells. Eur. J. Pharm. Sci. 105, 91–98 (2017).

    Article  PubMed  CAS  Google Scholar 

  142. Farabegoli, F. et al. Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways. Eur. J. Pharm. Sci. 47, 729–738 (2012).

    Article  PubMed  CAS  Google Scholar 

  143. Fiume, L. et al. Galloflavin prevents the binding of lactate dehydrogenase A to single stranded DNA and inhibits RNA synthesis in cultured cells. Biochem. Biophys. Res. Commun. 430, 466–469 (2013).

    Article  PubMed  CAS  Google Scholar 

  144. Wang, Z. et al. Bioactivity-guided identification and cell signaling technology to delineate the lactate dehydrogenase A inhibition effects of Spatholobus suberectus on breast cancer. PLoS ONE 8, e56631 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Billiard, J. et al. Quinoline 3-sulfonamides inhibit lactate dehydrogenase A and reverse aerobic glycolysis in cancer cells. Cancer Metab. 1, 19 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Granchi, C. et al. N-Hydroxyindole-based inhibitors of lactate dehydrogenase against cancer cell proliferation. Eur. J. Med. Chem. 46, 5398–5407 (2011).

    Article  PubMed  CAS  Google Scholar 

  147. Cui, W. et al. Discovery of 2-((3-cyanopyridin-2-yl)thio)acetamides as human lactate dehydrogenase A inhibitors to reduce the growth of MG-63 osteosarcoma cells: virtual screening and biological validation. Bioorg. Med. Chem. Lett. 26, 3984–3987 (2016).

    Article  PubMed  CAS  Google Scholar 

  148. Cao, W., Fang, L., Teng, S., Chen, H. & Wang, Z. Computer-aided discovery and biological characterization of human lactate dehydrogenase 5 inhibitors with anti-osteosarcoma activity. Bioorg. Med. Chem. Lett. 28, 2229–2233 (2018).

    Article  PubMed  CAS  Google Scholar 

  149. Purkey, H. E. et al. Cell active hydroxylactam inhibitors of human lactate dehydrogenase with oral bioavailability in mice. ACS Med. Chem. Lett. 7, 896–901 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Chen, C.-Y., Feng, Y., Chen, J.-Y. & Deng, H. Identification of a potent inhibitor targeting human lactate dehydrogenase A and its metabolic modulation for cancer cell line. Bioorg. Med. Chem. Lett. 26, 72–75 (2016).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors thank S. Bazin, O. and C. Courtin, Ensemble Contre le Mélanome, the Foundation Crédit Mutuel, Foundation Carrefour and the association Vaincre le Mélanome for their ongoing research funding support.

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G.C., S.F., V.Q. and C.R. researched data for this article, all authors made a substantial contribution to discussions of content, G.C., S.F., V.Q. and C.R. wrote the manuscript and all authors reviewed and/or edited the manuscript prior to submission.

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Correspondence to Caroline Robert.

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S.V. is a co-founder of Ribonexus. C.R. has acted as a consultant for Astra Zeneca, BMS, MSD, Pfizer, Pierre Fabre, Roche and Sanofi and is a co-founder of Ribonexus. The other authors declare no competing interests.

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Claps, G., Faouzi, S., Quidville, V. et al. The multiple roles of LDH in cancer. Nat Rev Clin Oncol 19, 749–762 (2022). https://doi.org/10.1038/s41571-022-00686-2

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