Targeting lactate metabolism for cancer therapeutics
Joanne R. Doherty, John L. Cleveland
Joanne R. Doherty, John L. Cleveland
Published September 3, 2013
Citation Information: J Clin Invest. 2013;123(9):3685-3692. https://doi.org/10.1172/JCI69741.
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Targeting lactate metabolism for cancer therapeutics

Abstract

Lactate, once considered a waste product of glycolysis, has emerged as a critical regulator of cancer development, maintenance, and metastasis. Indeed, tumor lactate levels correlate with increased metastasis, tumor recurrence, and poor outcome. Lactate mediates cancer cell intrinsic effects on metabolism and has additional non–tumor cell autonomous effects that drive tumorigenesis. Tumor cells can metabolize lactate as an energy source and shuttle lactate to neighboring cancer cells, adjacent stroma, and vascular endothelial cells, which induces metabolic reprogramming. Lactate also plays roles in promoting tumor inflammation and in functioning as a signaling molecule that stimulates tumor angiogenesis. Here we review the mechanisms of lactate production and transport and highlight emerging evidence indicating that targeting lactate metabolism is a promising approach for cancer therapeutics.

Authors

Joanne R. Doherty, John L. Cleveland

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Figure 1

Aerobic glycolysis and glutaminolysis in cancer cells.

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Aerobic glycolysis and glutaminolysis in cancer cells. Oncoproteins driv...
Oncoproteins drive the expression of genes involved in glycolysis and glutaminolysis, which results in production of excess amounts of lactate. Aberrant PI3K/AKT signaling and the transcriptional oncoproteins HIF-1α and MYC regulate the transcription of GLUT, HK2, TPI, ENO, and LDHA. HIF-1α induces the transcription of PFKFB3, which favors the production of F2,6BP, an allosteric activator of PFK1. The tumor suppressor protein p53 induces the expression of TIGAR, which dephosphorylates F2,6BP, blocking activation of PFK1 and inhibiting glycolysis. HIF-1α and MYC regulate the expression and splicing of the PKM2 isoform. MYC also regulates the expression of the glutamine transporter ASCT2 and GLS. Monocarboxylic acid transporters (MCTs) export lactate and protons and are regulated by HIF-1α and MYC. AcCoA, acetyl-CoA; ASP, aspartate; ASCT2, glutamine transporter; G, glucose; G6P, glucose-6-phosphate, F6P, fructose-6-phosphate; DHAP, dihydroxyacetone phosphate; GA3P, glyceraldehyde-3-phosphate; 1,3BPG, 1,3-bisphosphoglycerate; 2PG, 2-phosphoglycerate; 3PG, 3-phosphoglycerate; PEP, phosphoenolpyruvate; MDH, malate dehydrogenase; GOT, glutamic-oxaloacetic transaminase; GLUD1, glutamate dehydrogenase.