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  • However although lactic acid suppresses the activation of ef

    2022-05-24

    However, although lactic Cinchonidine receptor suppresses the activation of effector , rendering them unable to buffer intracellular acidity [32], other T cell subpopulations such as regulatory T cells (Tregs) exhibit metabolic adaptations in low-glucose, high-lactate environments. In particular, Treg transcription factor Foxp3 provides a metabolic advantage for Treg cells by stimulating the oxidation of extracellular lactate and mitochondrial activity that are necessary for Treg maintenance and function [33]. In addition, other myeloid cells resident within the TME (such as dendritic cells, DCs) are affected by lactate accumulation. Indeed, the accumulation of endogenous lactic acid skews DC differentiation toward a tolerogenic phenotype, that favours immunogenic tolerance. Furthermore, abundant Cinchonidine receptor acidification disturbs the production of inflammatory cytokines production that are necessary for TH1 cell polarization as well as for inflammatory DC differentiation [34]. In addition, lactate promotes antigen degradation, leading to failure of MHC class I antigen presentation, thereby rendering DC cell unable to prime antitumour responses [35].
    Lactate Import and Sensing Impacts on Cell Signalling Machinery Several lines of evidence indicate that lactate can promote gene expression in physiological contexts. For instance, in muscle cells lactate orchestrates an adaptive metabolic response to endurance training, involving a reactive oxygen species (ROS)-dependent/NRF2-mediated increase in MCT1 expression and subsequent lactate exploitation through the assembly of a mitochondrial lactate oxidation complex. This complex, located in the mitochondrial membrane in both normal and cancer cells, that comprises MCT1, its chaperone CD147, LDH, and cytochrome oxidase, allows the import and direct oxidation of lactate to pyruvate within mitochondria (Boxes 1–3) [36]. In neurons, astrocyte-derived lactate modifies the intracellular redox state through an imbalance in the NADH/NAD+ ratio, hence stimulating the N-methyl-D-aspartate (NMDA) receptors and ERK1/2-mediated expression of genes related to neuronal plasticity and long-term memory 37, 38. Lactate is also emerging as a metabolite that sustains tumour progression (Figure 1). For instance, lactate stabilizes hypoxia-inducible factor 1 (HIF-1) by inhibiting Fe2+ and 2-oxoglutarate-dependent prolyl hydroxylases (PHDs) [39], predominantly PHD2, that prevent VHL-mediated ubiquitination of HIF-1, thereby avoiding its proteasomal degradation. The lactate-dependent PHD2 impairment relies on lactate oxidation to pyruvate by LDHB, which results in competitive inhibition of PHD2 by pyruvate binding, and in HIF-1-mediated VEGF upregulation [39]. In normoxic non-malignant endothelial cells, lactate-induced HIF-1 activation promotes basic fibroblast growth factor (bFGF) and VEGFR2 expression, synergizing with lactate-induced tumour VEGF secretion 5, 40. A paracrine effect of lactate on HIF-1 and VEGF signalling has also been observed in MCT1-expressing oxidative cancer cells symbiotically coupled to glycolytic cancer cells [41]. Lactate import in normoxic oxidative cancer cells also involves HIF-1-mediated activation of carbonic anhydrase IX, thereby augmenting the aggressive features of cancer cells [42]. Recent findings showed that lactate-mediated inhibition of the PHD2/VHL system promotes a HIF-1-independent pathway which synergizes with the HIF-1-dependent machinery to sustain the response to hypoxia. In particular, lactate directly binds to the N-Myc downstream-regulated (NDRG3) protein and prevents its association with PHD2 and its degradation, ensuring long-lasting stabilization of the protein. The accumulation of NDRG3 results in Raf/ERK-mediated activation of an angiogenic and proliferative response, ensuring cell adaptation to prolonged hypoxia [43]. In endothelial cells, lactate induces a proangiogenic effect independently of HIF-1 activation. Indeed, Végran and colleagues demonstrated that MCT1-imported lactate mediates PHD- and ROS-dependent nuclear factor κB (NF-κB) activation, which supports autocrine IL-8 signalling, culminating in endothelial cell activation [44]. The particular role of lactate in this pathway is to integrate two different signals which cooperate to stabilize NF-κB: (i) ROS generation that accounts for redox-dependent stabilization of NF-κB, and (ii) impairment of PHD-dependent hydroxylation of IKKβ that leads to IκBα degradation and nuclear translocation of NF-κB. A similar signalling role was recently reported in a non-cell-autonomous mechanism of adaptive resistance to MET or EGFR inhibition [20], in which lactate secreted by Warburg-reprogrammed cancer cells instructs the surrounding CAFs to produce HGF through redox-dependent NF-κB activation, thus driving in vivo adaptive resistance.