Comparison of the effect of the aerobic glycolysis inhibitor dichloroacetate and of the Krebs cycle inhibitor LW6 on cellular and humoral alloimmunity

Eleftheriadis, Theodoros; Pissas, Georgios; Mavropoulos, Αthanasios; Liakopoulos, Vassilios; Stefanidis, Ioannis

doi:10.3892/br.2017.980

Cited by 9 publications

(4 citation statements)

References 37 publications

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“…These effects of DCA on T-cell differentiation are believed to be dependent on reactive oxygen species (ROS) production. 49 – 51 Recent studies have reported that inhibition of succinate dehydrogenase (a vital enzyme in the TCA cycle) significantly impaired proliferation and neutralization of mitochondrial membrane potential and yielded a decrease in cytokine secretion like IFN-γ, which are all integral parts of T cell functionality. 52 , 53 In addition, DCA suppressed macrophage migration by inhibiting glycolytic reprogramming.…”

Section: Discussionmentioning

confidence: 99%

HBV suppresses macrophage immune responses by impairing the TCA cycle through the induction of CS/PDHC hyperacetylation

Bei,

Chen,

Zhang

et al. 2023

Hepatology Communications

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Background: It is now understood that HBV can induce innate and adaptive immune response disorders by affecting immunosuppressive macrophages, resulting in chronic HBV infection. However, the underlying mechanism is not fully understood. Dysregulated protein acetylation can reportedly influence the differentiation and functions of innate immune cells by coordinating metabolic signaling. This study aims to assess whether HBV suppresses macrophage-mediated innate immune responses by affecting protein acetylation and to elucidate the underlying mechanisms of HBV immune escape. Methods: We investigated the effect of HBV on the acetylation levels of human THP-1 macrophages and identified potential targets of acetylation that play a role in glucose metabolism. Metabolic and immune phenotypes of macrophages were analyzed using metabolomic and flow cytometry techniques. Western blot, immunoprecipitation, and immunofluorescence were performed to measure the interactions between deacetylase and acetylated targets. Chronic HBV persistent infected mice were established to evaluate the role of activating the tricarboxylic acid (TCA) cycle in macrophages for HBV clearance. Results: Citrate synthase/pyruvate dehydrogenase complex hyperacetylation in macrophages after HBV stimulation inhibited their enzymatic activities and was associated with impaired TCA cycle and M2-like polarization. HBV downregulated Sirtuin 3 (SIRT3) expression in macrophages by means of the toll-like receptor 2 (TLR2)-NF-κB- peroxisome proliferatoractivated receptor γ coactivator 1α (PGC-1α) axis, resulting in citrate synthase/pyruvate dehydrogenase complex hyperacetylation. In vivo administration of the TCA cycle agonist dichloroacetate inhibited macrophage M2-like polarization and effectively reduced the number of serum HBV DNA copies. Conclusions: HBV-induced citrate synthase/pyruvate dehydrogenase complex hyperacetylation negatively modulates the innate immune response by impairing the TCA cycle of macrophages. This mechanism represents a potential therapeutic target for controlling HBV infection.

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Section: Discussionmentioning

confidence: 99%

HBV suppresses macrophage immune responses by impairing the TCA cycle through the induction of CS/PDHC hyperacetylation

Bei,

Chen,

Zhang

et al. 2023

Hepatology Communications

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“…However, it is unlikely that the inhibition of autophagic flux is the only way that LW6 increases the sensitivity to gemcitabine. Regulating other processes, such as tumor immunity [6] and cell metabolism [34], [35], by LW6 might also enhance the anti-cancer effects of gemcitabine [36]. Thus, it was worth to evaluate the anti-cancer effect of LW6 and LW6 plus gemcitabine in vivo since inhibition of several pathways might be superior to an inhibition of only autophagy.…”

Section: Discussionmentioning

confidence: 99%

LW6 enhances chemosensitivity to gemcitabine and inhibits autophagic flux in pancreatic cancer

Zhang

Kumstel

Jiang

et al. 2019

Journal of Advanced Research

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“…To ascertain whether MDH2 can be a pharmacological target of DIF-1, we needed to determine whether MDH2 inhibition by DIF-1 inhibits cell proliferation and/or promotes glucose uptake, or has no effect on these functions. We thus compared the effects of DIF-1 and the MDH2 inhibitor LW6 [24][25][26][27][28] on the growth of HeLa cells and 3T3-L1 cells in vitro (Figure 4A-D). In both HeLa and 3T3-L1 cells, DIF-1 at 10-40 µM dose-dependently suppressed cell growth (Figure 4A,C), as described previously [16].…”

Section: Effects Of An Mdh2 Inhibitor On the Growth Of Hela And 3t3-l...mentioning

confidence: 99%

Dictyostelium Differentiation-Inducing Factor 1 Promotes Glucose Uptake via Direct Inhibition of Mitochondrial Malate Dehydrogenase in Mouse 3T3-L1 Cells

Kubohara,

Fukunaga,

Shigenaga

et al. 2024

IJMS

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Differentiation-inducing factor 1 (DIF-1), found in Dictyostelium discoideum, has antiproliferative and glucose-uptake-promoting activities in mammalian cells. DIF-1 is a potential lead for the development of antitumor and/or antiobesity/antidiabetes drugs, but the mechanisms underlying its actions have not been fully elucidated. In this study, we searched for target molecules of DIF-1 that mediate the actions of DIF-1 in mammalian cells by identifying DIF-1-binding proteins in human cervical cancer HeLa cells and mouse 3T3-L1 fibroblast cells using affinity chromatography and liquid chromatography–tandem mass spectrometry and found mitochondrial malate dehydrogenase (MDH2) to be a DIF-1-binding protein in both cell lines. Since DIF-1 has been shown to directly inhibit MDH2 activity, we compared the effects of DIF-1 and the MDH2 inhibitor LW6 on the growth of HeLa and 3T3-L1 cells and on glucose uptake in confluent 3T3-L1 cells in vitro. In both HeLa and 3T3-L1 cells, DIF-1 at 10–40 μM dose-dependently suppressed growth, whereas LW6 at 20 μM, but not at 2–10 μM, significantly suppressed growth in these cells. In confluent 3T3-L1 cells, DIF-1 at 10–40 μM significantly promoted glucose uptake, with the strongest effect at 20 μM DIF-1, whereas LW6 at 2–20 μM significantly promoted glucose uptake, with the strongest effect at 10 μM LW6. Western blot analyses showed that LW6 (10 μM) and DIF-1 (20 μM) phosphorylated and, thus, activated AMP kinase in 3T3-L1 cells. Our results suggest that MDH2 inhibition can suppress cell growth and promote glucose uptake in the cells, but appears to promote glucose uptake more strongly than it suppresses cell growth. Thus, DIF-1 may promote glucose uptake, at least in part, via direct inhibition of MDH2 and a subsequent activation of AMP kinase in 3T3-L1 cells.

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Comparison of the effect of the aerobic glycolysis inhibitor dichloroacetate and of the Krebs cycle inhibitor LW6 on cellular and humoral alloimmunity

Cited by 9 publications

References 37 publications

HBV suppresses macrophage immune responses by impairing the TCA cycle through the induction of CS/PDHC hyperacetylation

HBV suppresses macrophage immune responses by impairing the TCA cycle through the induction of CS/PDHC hyperacetylation

LW6 enhances chemosensitivity to gemcitabine and inhibits autophagic flux in pancreatic cancer

Dictyostelium Differentiation-Inducing Factor 1 Promotes Glucose Uptake via Direct Inhibition of Mitochondrial Malate Dehydrogenase in Mouse 3T3-L1 Cells

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