Lactate Can Regulate Cell Cycle Progression

Lactate (lactic acid) is the byproduct of the metabolism of glucose in the absence of oxygen, referred to as anaerobic glycolysis. The major source of lactate is glucose metabolism in red blood cells (erythrocytes) since these cells lack mitochondria which are required for complete oxidation of glucose to CO2 and water. Under intense activity, skeletal muscle cells also produce lactate.

The major fate of lactate is to be taken up by hepatocytes of the liver where is can be oxidized to pyruvate and then 2 molecules of pyruvate can be used to make new glucose via the metabolic pathway of gluconeogenesis. The de novo glucose can then be released back to the blood to be utilized by red blood cells and other tissues such as the brain or skeletal muscle.

However, non-glucose producing functions for lactate have been identified. Lactate production by cancer cells contributes to both the metabolically active state of cancer cells but also to the immune system evasion by cancer cells. The conversion of pyruvate into lactate is enhanced in the context of the activated transcription factor, HIF-1, since this transcription factor activates the expression of the LDHA (lactate dehydrogenase A) gene. The increased production of lactate, by cancer cells, contributes to the acidification of the tumor microenvironment which, in turn, promotes further activation of the HIF-1 pathway. Lactate accumulation also results in pyruvate accumulation in cancer cells. Pyruvate is a known inhibitor of the prolyl hydroxylases that hydroxylate the HIF1α subunit proteins. Loss of HIF1α proline hydroxylation results in increased HIF1α stability and, therefore, increased HIF-1 transcriptional activity. Thus, accumulation of lactate and pyruvate, which occurs as a result of both altered pyruvate kinase gene expression and activation of the HIF-1 pathway, further promotes activation of the HIF-1 pathway leading to a controlled and enhanced metabolic profile within cancer cells.

Lactate is the ligand for the G-protein coupled receptor (GPCR) encoded by the HCAR1 gene. The receptor is a member of the hydroxycarboxylic acid (HCA) receptor family and as such is identified HCA1. Of significance to cancer cell proliferation is that the HCA1 receptor is expressed on cancer cells and dendritic cells of the immune system. These sites of expression contribute to the role of lactate in overall cancer metabolism and immune system evasion. Due to the altered metabolism of glucose in cancer cells they produce large amounts of lactate. The lactate then binds to HCA1 receptors on these same cells resulting in the activation of a transcription program that contributes to immune evasion. One significant gene whose transcription is enhanced in lactate-stimulated cancer cells is CD274. The protein encoded by the CD274 gene is called programmed death ligand 1 (PD-L1). The role of PD-L1 is suppression of the adaptive immune response, thereby contributing to reduced immune system activation of T-cells. When HCA1 is activated on dendritic cells of the immune system they express reduced levels of MHC molecules as well as the interleukins, IL-6 and IL-12. IL-12 is involved in the maturation of immature T-cells and thus, reduce release of IL-12 by dendritic cells further contributes to reduced T-cell-mediated adaptive immunity.

Most recently lactate has been found to regulate cell cycle progression as demonstrated by a recent publication in the prestigious journal, Nature: 

Lactate regulates cell cycle by remodelling the anaphase promoting complex

The results presented in this recent publication provide further evidence for the mechanisms by which lactate promotes the proliferation of cancer cells. The results show that the E2 ubiquitin-conjugating enzyme (UBE2C), that is a transient partner of the anaphase-promoting complex/cyclosome (APC/C), directly interacts with lactate and that this interaction results in altered cell cycle progression. When lactate levels rise there is increased interaction between UBE2C and APC/C via a stimulation of the SUMOylation of APC4. APC4 is a component of the APC/C and functions as a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The mechanism by which lactate alters the SUMOylation of APC4, as well as other cell cycle regulatory components, is by forming a complex with Zn²⁺ in the active site of the SUMO protease, SENP1. The interaction of lactate with SENP1 results in the inhibition of the deSUMOylation of proteins such as APC4. This in turn promotes APC/C interaction with UBE2C which then ubiquitylates several cell cycle regulatory proteins such as cyclin B1 and securin. The net effect is progression of the cell cycle to mitosis and cell division. When lactate levels are low the reverse is true, SENP1 deSUMOylates APC4 which prevents APC/C and UBE2C interaction causing cells to remain at the G₂-M transition.