Tumor Metabolism: Cancer Cells Give and Take Lactate

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2008 Nov 27

PMID 19033652

Citations 157

Authors

Gregg L Semenza

Affiliations

Soon will be listed here.

Abstract

Tumors contain well-oxygenated (aerobic) and poorly oxygenated (hypoxic) regions, which were thought to utilize glucose for oxidative and glycolytic metabolism, respectively. In this issue of the JCI, Sonveaux et al. show that human cancer cells cultured under hypoxic conditions convert glucose to lactate and extrude it, whereas aerobic cancer cells take up lactate via monocarboxylate transporter 1 (MCT1) and utilize it for oxidative phosphorylation (see the related article beginning on page 3930). When MCT1 is inhibited, aerobic cancer cells take up glucose rather than lactate, and hypoxic cancer cells die due to glucose deprivation. Treatment of tumor-bearing mice with an inhibitor of MCT1 retarded tumor growth. MCT1 expression was detected exclusively in nonhypoxic regions of human cancer biopsy samples, and in combination, these data suggest that MCT1 inhibition holds potential as a novel cancer therapy.

Citing Articles

Aging, cancer, and autophagy: connections and therapeutic perspectives.

Zapateria B, Arias E Front Mol Biosci. 2025; 11:1516789.

PMID: 39935707 PMC: 11811537. DOI: 10.3389/fmolb.2024.1516789.

Engineered hypoxia-responsive albumin nanoparticles mediating mitophagy regulation for cancer therapy.

Wang W, Yao S, Luo J, Ding C, Huang Q, Yang Y Nat Commun. 2025; 16(1):596.

PMID: 39799105 PMC: 11724902. DOI: 10.1038/s41467-025-55905-y.

Cancer-associated fibroblasts: heterogeneity, tumorigenicity and therapeutic targets.

Lv K, He T Mol Biomed. 2024; 5(1):70.

PMID: 39680287 PMC: 11649616. DOI: 10.1186/s43556-024-00233-8.

New insights into the roles of lactylation in cancer.

Zhu Y, Liu W, Luo Z, Xiao F, Sun B Front Pharmacol. 2024; 15:1412672.

PMID: 39502530 PMC: 11534861. DOI: 10.3389/fphar.2024.1412672.

The Research Progress of Metformin Regulation of Metabolic Reprogramming in Malignant Tumors.

Sui Q, Yang H, Hu Z, Jin X, Chen Z, Jiang W Pharm Res. 2024; 41(11):2143-2159.

PMID: 39455505 DOI: 10.1007/s11095-024-03783-2.

References

Vaupel P, Mayer A . Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev. 2007; 26(2):225-39. DOI: 10.1007/s10555-007-9055-1. View

Ebert B, Firth J, Ratcliffe P . Hypoxia and mitochondrial inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences. J Biol Chem. 1995; 270(49):29083-9. DOI: 10.1074/jbc.270.49.29083. View

Cardenas-Navia L, Mace D, Richardson R, Wilson D, Shan S, Dewhirst M . The pervasive presence of fluctuating oxygenation in tumors. Cancer Res. 2008; 68(14):5812-9. DOI: 10.1158/0008-5472.CAN-07-6387. View

Gatenby R, Gillies R . Why do cancers have high aerobic glycolysis?. Nat Rev Cancer. 2004; 4(11):891-9. DOI: 10.1038/nrc1478. View

Ullah M, Davies A, Halestrap A . The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem. 2006; 281(14):9030-7. DOI: 10.1074/jbc.M511397200. View

Sonveaux P, Vegran F, Schroeder T, Wergin M, Verrax J, Rabbani Z . Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008; 118(12):3930-42. PMC: 2582933. DOI: 10.1172/JCI36843. View

Shimoda L, Fallon M, Pisarcik S, Wang J, Semenza G . HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes. Am J Physiol Lung Cell Mol Physiol. 2006; 291(5):L941-9. DOI: 10.1152/ajplung.00528.2005. View

Papandreou I, Cairns R, Fontana L, Lim A, Denko N . HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006; 3(3):187-97. DOI: 10.1016/j.cmet.2006.01.012. View

DeBerardinis R, Sayed N, Ditsworth D, Thompson C . Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008; 18(1):54-61. PMC: 2476215. DOI: 10.1016/j.gde.2008.02.003. View

10.

Semenza G, Jiang B, Leung S, Passantino R, Concordet J, Maire P . Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem. 1996; 271(51):32529-37. DOI: 10.1074/jbc.271.51.32529. View

11.

Kerbel R . Tumor angiogenesis. N Engl J Med. 2008; 358(19):2039-49. PMC: 4542009. DOI: 10.1056/NEJMra0706596. View

12.

Melillo G . Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev. 2007; 26(2):341-52. DOI: 10.1007/s10555-007-9059-x. View

13.

Yun Z, Maecker H, Johnson R, Giaccia A . Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia. Dev Cell. 2002; 2(3):331-41. DOI: 10.1016/s1534-5807(02)00131-4. View

14.

Seagroves T, RYAN H, Lu H, Wouters B, Knapp M, Thibault P . Transcription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells. Mol Cell Biol. 2001; 21(10):3436-44. PMC: 100265. DOI: 10.1128/MCB.21.10.3436-3444.2001. View

15.

Zhang H, Bosch-Marce M, Shimoda L, Tan Y, Baek J, Wesley J . Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 2008; 283(16):10892-903. PMC: 2447655. DOI: 10.1074/jbc.M800102200. View

16.

Liao D, Johnson R . Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 2007; 26(2):281-90. DOI: 10.1007/s10555-007-9066-y. View

17.

Kroemer G, Pouyssegur J . Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell. 2008; 13(6):472-82. DOI: 10.1016/j.ccr.2008.05.005. View

18.

Kim J, Tchernyshyov I, Semenza G, Dang C . HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; 3(3):177-85. DOI: 10.1016/j.cmet.2006.02.002. View

19.

Wykoff C, Beasley N, Watson P, Turner K, Pastorek J, Sibtain A . Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 2001; 60(24):7075-83. View

20.

Helmlinger G, Yuan F, Dellian M, Jain R . Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med. 1997; 3(2):177-82. DOI: 10.1038/nm0297-177. View