bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2021–09–05
five papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Glutamine metabolism regulates endothelial to hematopoietic transition and hematopoietic lineage specification.
  2. Autophagy promotes growth of tumors with high mutational burden by inhibiting a T-cell immune response.
  3. Nanoparticle-Mediated Inhibition of Mitochondrial Glutaminolysis to Amplify Oxidative Stress for Combination Cancer Therapy.
  4. Potassium and Sodium Channels and the Warburg Effect: Biophysical Regulation of Cancer Metabolism.
  5. The predominant role of glucose as a building block and precursor of reducing equivalents.
  1. Sci Rep. 2021 Sep 02. 11(1): 17589
    Glutamine metabolism regulates endothelial to hematopoietic transition and hematopoietic lineage specification.
    Leal Oburoglu, Els Mansell, Niels-Bjarne Woods.
      During hematopoietic development, definitive hematopoietic cells are derived from hemogenic endothelial (HE) cells through a process known as endothelial to hematopoietic transition (EHT). During EHT, transitioning cells proliferate and undergo progressive changes in gene expression culminating in the new cell identity with corresponding changes in function, phenotype and morphology. However, the metabolic pathways fueling this transition remain unclear. We show here that glutamine is a crucial regulator of EHT and a rate limiting metabolite in the hematopoietic differentiation of HE cells. Intriguingly, different hematopoietic lineages require distinct derivatives of glutamine. While both derivatives, α-ketoglutarate and nucleotides, are required for early erythroid differentiation of HE during glutamine deprivation, lymphoid differentiation relies on α-ketoglutarate alone. Furthermore, treatment of HE cells with α-ketoglutarate in glutamine-free conditions pushes their differentiation towards lymphoid lineages both in vitro and in vivo, following transplantation into NSG mice. Thus, we report an essential role for glutamine metabolism during EHT, regulating both the emergence and the specification of hematopoietic cells through its various derivatives.
    DOI:  https://doi.org/10.1038/s41598-021-97194-7
  2. Nat Cancer. 2020 Sep;1(9): 923-934
    Autophagy promotes growth of tumors with high mutational burden by inhibiting a T-cell immune response.
    Laura Poillet-Perez, Daniel W Sharp, Yang Yang, Saurabh V Laddha, Maria Ibrahim, Praveen K Bommareddy, Zhixian Sherrie Hu, Joshua Vieth, Michael Haas, Marcus W Bosenberg, Joshua D Rabinowitz, Jian Cao, Jun-Lin Guan, Shridar Ganesan, Chang S Chan, Janice M Mehnert, Edmund C Lattime, Eileen White.
      Macroautophagy (hereafter autophagy) degrades and recycles intracellular components to sustain metabolism and survival during starvation. Host autophagy promotes tumor growth by providing essential tumor nutrients. Autophagy also regulates immune cell homeostasis and function and suppresses inflammation. Although host autophagy does not promote a T-cell anti-tumor immune response in tumors with low tumor mutational burden (TMB), whether this was the case in tumors with high TMB was not known. Here we show that autophagy, especially in the liver, promotes tumor immune tolerance by enabling regulatory T-cell function and limiting stimulator of interferon genes, T-cell response and interferon-γ, which enables growth of high-TMB tumors. We have designated this as hepatic autophagy immune tolerance. Autophagy thereby promotes tumor growth through both metabolic and immune mechanisms depending on mutational load and autophagy inhibition is an effective means to promote an antitumor T-cell response in high-TMB tumors.
    DOI:  https://doi.org/10.1038/s43018-020-00110-7
  3. Nano Lett. 2021 Sep 02.
    Nanoparticle-Mediated Inhibition of Mitochondrial Glutaminolysis to Amplify Oxidative Stress for Combination Cancer Therapy.
    Lei Xu, Rui Xu, Phei Er Saw, Jun Wu, Si-Xue Cheng, Xiaoding Xu.
      Selective amplification of reactive oxygen species (ROS) generation in tumor cells has been recognized as an effective strategy for cancer therapy. However, an abnormal tumor metabolism, especially the mitochondrial glutaminolysis, could promote tumor cells to generate high levels of antioxidants (e.g., glutathione) to evade ROS-induced damage. Here, we developed a tumor-targeted nanoparticle (NP) platform for effective breast cancer therapy via combining inhibition of mitochondrial glutaminolysis and chemodynamic therapy (CDT). This NP platform is composed of bovine serum albumin (BSA), ferrocene, and purpurin. After surface decoration with a tumor-targeting aptamer and then intravenous administration, this NP platform could target tumor cells and release ferrocene to catalyze hydrogen peroxide (H2O2) into the hydroxyl radical (·OH) for CDT. More importantly, purpurin could inhibit mitochondrial glutaminolysis to concurrently prevent the nutrient supply for tumor cells and disrupt intracellular redox homeostasis for enhanced CDT, ultimately leading to the combinational inhibition of tumor growth.
    Keywords:  Reactive oxygen species; chemodynamic therapy; combination cancer therapy; glutaminolysis; nanoparticle
    DOI:  https://doi.org/10.1021/acs.nanolett.1c02073
  4. Bioelectricity. 2019 Sep 01. 1(3): 188-200
    Potassium and Sodium Channels and the Warburg Effect: Biophysical Regulation of Cancer Metabolism.
    Jessica Iorio, Giulia Petroni, Claudia Duranti, Elena Lastraioli.
      Ion channels are progressively emerging as a novel class of membrane proteins expressed in several types of human cancers and regulating the different aspects of cancer cell behavior. The metabolism of cancer cells, usually composed by a variable proportion of respiration, glycolysis, and glutaminolysis, leads to the excessive production of acidic metabolic products. The presence of these acidic metabolites inside the cells results in intracellular acidosis, and hinders survival and proliferation. For this reason, tumor cells activate mechanisms of pH control that produce a constitutive increase in intracellular pH (pHi) that is more acidic than the extracellular pH (pHe). This condition forms a perfect microenvironment for metastatic progression and may be permissive for some of the acquired characteristics of tumors. Recent analyses have revealed complex interconnections between oncogenic activation, ion channels, hypoxia signaling and metabolic pathways that are dysregulated in cancer. Here, we summarize the molecular mechanisms of the Warburg effect and hypoxia and their association. Moreover, we discuss the recent findings concerning the involvement of ion channels in various aspects of the Warburg effect and hypoxia, focusing on the role of Na+ and K+ channels in hypoxic and metabolic reprogramming in cancer.
    Keywords:  Warburg effect; cancer; ion channels
    DOI:  https://doi.org/10.1089/bioe.2019.0017
  5. Curr Opin Clin Nutr Metab Care. 2021 Aug 26.
    The predominant role of glucose as a building block and precursor of reducing equivalents.
    Lubos Sobotka, Ondrej Sobotka.
       PURPOSE OF REVIEW: Stores of glucose (Glc) in our body are small compared with protein and lipid. Therefore, at times of famines or trauma/disease-related starvation, glucose utilization must be limited only to pathways that can only run with glucose carbon as substrate. We will try to outline how insulin resistance drives these pathways and inhibits glucose oxidation in the stressed organism.
    RECENT FINDINGS: Glc is a basic substrate for a variety of other biomolecules like nucleic acids, amino acids, proteoglycans, mucopolysaccharides and lipids. It is essential for the formation of reducing equivalents, indispensable for anabolic, antioxidative, regulatory and immune processes. As a result, a continuous Glc turnover/cycle is essential to secure at all times the Glc requirements for nonoxidative pathways mentioned above but then requires introduction of extra glucose or other intermediates into the cycle. The production of ATP through complete Glc oxidation occurs only when Glc intake is higher than required for its nonoxidative metabolism. Insulin resistance and decreased Glc oxidation indicate that requirements of Glc for anabolic pathways are high.
    SUMMARY: Glc is an important building block for anabolic reactions and substrate for reducing equivalents formation. Insulin resistance prevents irreversible Glc oxidation and stimulates Glc production during stress or growth. Glc is only oxidized when intake is in excess of its anabolic requirements.
    DOI:  https://doi.org/10.1097/MCO.0000000000000786
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