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.

Figure 1. Aerobic glycolysis and glutaminolysis in cancer cells.

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.

Figure 2. Lactate dehydrogenase activity and tetramers.

(A) LDH mediates the redox-coupled conversion between lactate and NAD⁺ with pyruvate and NADH. (B) The functional LDH enzyme is a tetramer containing differing ratios of the LDHA and LDHB subunits. The composition of the five LDH tetramers is shown.

Figure 3. Three models of lactate shuttling in cancer.

(A) The reverse Warburg effect occurs when cancer cells secrete hydrogen peroxide, which is thought to generate a pseudo-hypoxic environment in the stroma. In turn, this induces HIF-1α, MCT4 expression, and glycolysis in stromal fibroblasts, which then efflux excess lactate via MCT4. Stromal-derived lactate is then imported by tumor cells via MCT1 and used as an oxidative metabolite. (B) In metabolic symbiosis, tumor cells in hypoxic regions of the tumor efflux lactate through MCT4, which is then imported by tumor cells in less hypoxic regions via MCT1 and used as an oxidative metabolite. This shuttling facilitates delivery of glucose to the hypoxic regions of the tumor. (C) In the vascular endothelial lactate shuttle, tumor cells efflux lactate via MCT4, which is imported by vascular endothelial cells by MCT1. Lactate is then converted to pyruvate, which activates HIF-1α and NF-κB/IL-8 signaling.