Browsing by Subject "Metabolic reprogramming"

Now showing 1 - 3 of 3
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    Acid–base Homeostasis and Implications to the Phenotypic Behaviors of Cancer
    (Elsevier, 2023) Zhou, Yi; Chang, Wennan; Lu, Xiaoyu; Wang, Jin; Zhang, Chi; Xu, Ying; Medical and Molecular Genetics, School of Medicine
    Acid-base homeostasis is a fundamental property of living cells, and its persistent disruption in human cells can lead to a wide range of diseases. In this study, we conducted a computational modeling analysis of transcriptomic data of 4750 human tissue samples of 9 cancer types in The Cancer Genome Atlas (TCGA) database. Built on our previous study, we quantitatively estimated the average production rate of OH- by cytosolic Fenton reactions, which continuously disrupt the intracellular pH (pHi) homeostasis. Our predictions indicate that all or at least a subset of 43 reprogrammed metabolisms (RMs) are induced to produce net protons (H+) at comparable rates of Fenton reactions to keep the pHi stable. We then discovered that a number of well-known phenotypes of cancers, including increased growth rate, metastasis rate, and local immune cell composition, can be naturally explained in terms of the Fenton reaction level and the induced RMs. This study strongly suggests the possibility to have a unified framework for studies of cancer-inducing stressors, adaptive metabolic reprogramming, and cancerous behaviors. In addition, strong evidence is provided to demonstrate that a popular view that Na+/H+ exchangers along with lactic acid exporters and carbonic anhydrases are responsible for the intracellular alkalization and extracellular acidification in cancer may not be justified.
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    Metabolic interventions: A new insight into the cancer immunotherapy
    (Elsevier, 2021) Yu, Tao; Dong, Tianhan; Eyvani, Haniyeh; Fang, Yuanzhang; Wang, Xiyu; Zhang, Xinna; Lu, Xiongbin; Medical and Molecular Genetics, School of Medicine
    Metabolic reprogramming confers cancer cells plasticity and viability under harsh conditions. Such active alterations lead to cell metabolic dependency, which can be exploited as an attractive target in development of effective antitumor therapies. Similar to cancer cells, activated T cells also execute global metabolic reprogramming for their proliferation and effector functions when recruited to the tumor microenvironment (TME). However, the high metabolic activity of rapidly proliferating cancer cells can compete for nutrients with immune cells in the TME, and consequently, suppressing their anti-tumor functions. Thus, therapeutic strategies could aim to restore T cell metabolism and anti-tumor responses in the TME by targeting the metabolic dependence of cancer cells. In this review, we highlight current research progress on metabolic reprogramming and the interplay between cancer cells and immune cells. We also discuss potential therapeutic intervention strategies for targeting metabolic pathways to improve cancer immunotherapy efficacy.
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    Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype
    (Frontiers, 2019-05-07) Min, Byong-Keol; Park, Sungmi; Kang, Hyeon-Ji; Kim, Dong Wook; Ham, Hye Jin; Ha, Chae-Myeong; Choi, Byung-Jun; Lee, Jung Yi; Oh, Chang Joo; Yoo, Eun Kyung; Kim, Hui Eon; Kim, Byung-Gyu; Jeon, Jae-Han; Hyeon, Do Young; Hwang, Daehee; Kim, Yong-Hoon; Lee, Chul-Ho; Lee, Taeho; Kim, Jung-whan; Choi, Yeon-Kyung; Park, Keun-Gyu; Chawla, Ajay; Lee, Jongsoon; Harris, Robert A.; Lee, In-Kyu; Biochemistry and Molecular Biology, School of Medicine
    Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.