Similarly, HIF-1 modulated a switch from cytochrome C oxidase subunit IV isoform 1 (COX4-1) to COX4-2, a less active subunit in ETC complex IV to prevent excessive ROS accumulation under hypoxia [47] (Figure 3) (Table 1)

Similarly, HIF-1 modulated a switch from cytochrome C oxidase subunit IV isoform 1 (COX4-1) to COX4-2, a less active subunit in ETC complex IV to prevent excessive ROS accumulation under hypoxia [47] (Figure 3) (Table 1). metabolism [27] (Physique 2B), thus preventing deleterious buildup of mitochondrial ROS under hypoxia. Furthermore, glycolytic metabolite, 3-phosphoglyceric acid (3PG), enters serine synthesis pathway (SSP) generating serine, which enters the folate cycle to provide a source of nicotinamide adenine dinucleotide phosphate (NADPH) to counteract ROS. Interestingly, enzymes in the SSP and folate cycle are consistently induced by hypoxia/HIFs [28]. Since induction of oxidative stress is an important mechanism for antitumoral effect of TKIs [29], metabolic rewiring under hypoxia contributes to drug resistance by lowering ROS in TKI-treated HCC. Moreover, levels of metabolites, including glucose, lactate and adenosine were altered in TME that SB-334867 free base collectively shape an immunosuppressive environment to greatly hinder the efficacy of ICIs in HCC. Open in a separate window Physique 2 Hypoxia-inducible factors (HIFs) divert metabolites from tricarboxylic acid cycle (TCA) cycle to glycolysis under hypoxia. (a) Under normoxia, glucose is converted to pyruvate during glycolysis. Pyruvate is usually then converted to acetyl coenzyme A (acetyl-CoA), which fuels the TCA cycle for maximum adenosine triphosphate (ATP) production with ample oxygen (O2) supply. (b) Under hypoxia, metabolism is switched from oxidative to glycolytic metabolism by HIF-dependent upregulation of pyruvate dehydrogenase kinase 1 (PDK1) and (lactate dehydrogenase A) LDHA. Lactate export is usually promoted to prevent excessive intracellular lactate accumulation, which may lead to cytoplasmic acidification. Serine synthesis pathway (SSP) and its downstream folate cycle are activated. Folate cycle produces a major antioxidant, nicotinamide adenine dinucleotide phosphate (NADPH), to counteract oxidative stress under hypoxia. Mitochondrial activity and biogenesis are suppressed to reduce mitochondrial reactive oxygen species (ROS) production. Genes or pathways highlighted in reddish: upregulated by HIFs. Genes or pathways highlighted in blue: downregulated by HIFs. Open in a separate window Physique 3 Electron transport chain (ETC). ETC is located at mitochondrial inner membrane (MIM). Electron donors produced from glycolysis and TCA cycle, nicotinamide adenine dinucleotide (NADH) and flavin adenine SB-334867 free base dinucleotide (FADH2), and succinate (glucose intermediate) donate electrons to the ETC. Electrons pass through ETC complex I to Ednra IV and finally to O2, the final electron accepter. Electron circulation drives H+ export to the intermembrane space, creating a transmembrane electrical potential to drive ATP synthesis. Premature electron leakage prospects to ROS accumulation, especially at complex I and complex III. 3.1. HIF-Mediated Induction of Glucose Metabolism under Hypoxia Glucose uptake and glycolysis are activated in hypoxic HCC cells. HIF-1 induces the expression of solute carrier family 2 member 1 (and and and and and significantly inhibited lactate-induced PD-L1 expression [78]. Lactate-activated GPR81 contributed to nuclear translocation of a transcriptional coactivator, WW domain name made up of transcription regulator (TAZ), which then forms a complex with transcriptional enhanced associate domain name (TEAD), a transcription factor that promotes PD-L1 expression [78]. Open in a separate window Physique 4 HIF-induced metabolic reprogramming under hypoxia creates an immunosuppressive TME. HIF-mediated induction of lactate metabolism and adenosinergic metabolism leads to SB-334867 free base the accumulation of oncometabolites, including lactate, adenosine monophosphate (AMP) and adenosine at TME that inhibits anti-tumoral immune cells and promotes growth of protumoral immune cells, resulting in an immunosuppressive TME that aids immune evasion of tumor cells. In CD8+ T cells, lactate induced apoptosis, inhibited proliferation, decreased IFN production, intracellular perforin and granzyme-B levels [79] (Physique 4). High lactate level at TME inhibited lactate efflux and promoted lactate influx, leading to the accumulation of cytoplasmic lactate, causing intracellular acidification and reduction of CD8+ T cell viability [79]. Removal of lactate from culture medium significantly restored cytokine production and cytotoxicity of CD8+ T cells [79], suggesting that lactate hindered proper function of CD8+ T cells. Similarly, lactate induced apoptosis, reduced perforin, granzyme B production and suppressed expression of activating receptor, NKp46, in NK cells [80] (Physique 4). Lactate-treated NK cells also exhibited intracellular acidification [80]. Additionally, in mice tumor associated macrophage, lactate promoted a shift from anti-tumoral M1 phenotype to protumoral M2 phenotype in a HIF-1-dependent manner [81] (Physique 4). Moreover, lactate induced other M2 markers, including CD206 and CCL17, by activating G protein-coupled receptor 132 (Gpr132) responsible for extracellular lactate sensing [82]. Importantly, only lactate, but not low pH or M2 macrophage activating cytokine, IL-4, activated Gpr132 signaling to promote M1-to-M2 switch in macrophage [82]. M2 polarization was abrogated upon removal of lactate from culture medium [82]. Progression of malignancy with high lactate content was significantly halted in knockout mice with reduced tumor-associated M2 macrophages, indicating the importance of lactate/Gpr132 axis in inducing M2 macrophages [82]. Moreover, lactate increased the proportion of intratumoral immunosuppressive cells, Treg and MDSCs [83,84] (Physique 4). Interestingly, intratumoral Treg overexpressed MCT1 to take up lactate from TME to sustain OXPHOS [85]..