bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023–05–07
eleven papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Amino acid metabolism, redox balance and epigenetic regulation in cancer.
  2. Amino acid metabolism regulated by lncRNAs: the propellant behind cancer metabolic reprogramming.
  3. Tumor-targeted nanoflowers regulate glutamine metabolism and amplify oxidative stress for synergistic therapy.
  4. Targeting cellular respiration as a therapeutic strategy in glioblastoma.
  5. Noncanonical role of singleminded-2s in mitochondrial respiratory chain formation in breast cancer.
  6. Redox homeostasis and beyond: The role of wild-type Isocitrate Dehydrogenases for the pathogenesis of Glioblastoma.
  7. Histone deacetylase inhibitor belinostat regulates metabolic reprogramming in killing KRAS-mutant human lung cancer cells.
  8. Methionine restriction constrains lipoylation and activates mitochondria for nitrogenic synthesis of amino acids.
  9. The tricarboxylic acid (TCA) cycle: a malleable metabolic network to counter cellular stress.
  10. The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer.
  11. A novel GSH-activable theranostic probe containing kinase inhibitor for synergistic treatment and selective imaging of tumor cells.
  1. FEBS J. 2023 May 02.
    Amino acid metabolism, redox balance and epigenetic regulation in cancer.
    Xiang Li, Hong-Sheng Zhang.
      Amino acids act as the versatile nutrients driving cell growth and survival, especially in cancer cells. Amino acid metabolism comprises numerous metabolic networks and is closely linked with intracellular redox balance and epigenetic regulation. Reprogrammed amino acid metabolism has been recognized as a ubiquitous feature in tumor cells. This review outlines the metabolism of several primary amino acids in cancer cells and highlights the pivotal role of amino acid metabolism in sustaining redox homeostasis and regulating epigenetic modification in response to oxidative and genetic stress in cancer cells.
    Keywords:  amino acids; cancer; epigenetic regulation; metabolism; redox balance
    DOI:  https://doi.org/10.1111/febs.16803
  2. Cell Commun Signal. 2023 May 01. 21(1): 87
    Amino acid metabolism regulated by lncRNAs: the propellant behind cancer metabolic reprogramming.
    Qifan Hu, Yutong Li, Dan Li, Yi Yuan, Keru Wang, Lu Yao, Zhujun Cheng, Tianyu Han.
      Metabolic reprogramming is one of the main characteristics of cancer cells and plays pivotal role in the proliferation and survival of cancer cells. Amino acid is one of the key nutrients for cancer cells and many studies have focused on the regulation of amino acid metabolism, including the genetic alteration, epigenetic modification, transcription, translation and post-translational modification of key enzymes in amino acid metabolism. Long non-coding RNAs (lncRNAs) are composed of a heterogeneous group of RNAs with transcripts of more than 200 nucleotides in length. LncRNAs can bind to biological molecules such as DNA, RNA and protein, regulating the transcription, translation and post-translational modification of target genes. Now, the functions of lncRNAs in cancer metabolism have aroused great research interest and significant progress has been made. This review focuses on how lncRNAs participate in the reprogramming of amino acid metabolism in cancer cells, especially glutamine, serine, arginine, aspartate, cysteine metabolism. This will help us to better understand the regulatory mechanism of cancer metabolic reprogramming and provide new ideas for the development of anti-cancer drugs. Video Abstract.
    Keywords:  Amino acid metabolism; Cancer; Long non-coding RNA; Metabolic reprogramming
    DOI:  https://doi.org/10.1186/s12964-023-01116-1
  3. Chem Commun (Camb). 2023 May 05.
    Tumor-targeted nanoflowers regulate glutamine metabolism and amplify oxidative stress for synergistic therapy.
    Mengzhen Wang, Kaixian Wang, Xiaohan Liu, Mingwan Shi, Huiwen Zhang, Xia Zhang, Ruyue Wei, Na Li, Wei Pan, Bo Tang.
      We designed and synthesized tumor-targeted nanoflowers to inhibit glutamine metabolism and amplify oxidative stress, which could synergistically suppress tumor growth.
    DOI:  https://doi.org/10.1039/d3cc00487b
  4. Oncotarget. 2023 May 04. 14 419-425
    Targeting cellular respiration as a therapeutic strategy in glioblastoma.
    Enyuan Shang, Trang Thi Thu Nguyen, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin.
      While glycolysis is abundant in malignancies, mitochondrial metabolism is significant as well. Mitochondria harbor the enzymes relevant for cellular respiration, which is a critical pathway for both regeneration of reduction equivalents and energy production in the form of ATP. The oxidation of NADH2 and FADH2 are fundamental since NAD and FAD are the key components of the TCA-cycle that is critical to entertain biosynthesis in cancer cells. The TCA-cycle itself is predominantly fueled through carbons from glucose, glutamine, fatty acids and lactate. Targeting mitochondrial energy metabolism appears feasible through several drug compounds that activate the CLPP protein or interfere with NADH-dehydrogenase, pyruvate-dehydrogenase, enzymes of the TCA-cycle and mitochondrial matrix chaperones. While these compounds have demonstrated anti-cancer effects in vivo, recent research suggests which patients most likely benefit from such treatments. Here, we provide a brief overview of the status quo of targeting mitochondrial energy metabolism in glioblastoma and highlight a novel combination therapy.
    Keywords:  carbon tracing; central carbon metabolism; glioblastoma; lactate; metabolism
    DOI:  https://doi.org/10.18632/oncotarget.28424
  5. Exp Mol Med. 2023 May 01.
    Noncanonical role of singleminded-2s in mitochondrial respiratory chain formation in breast cancer.
    Steven W Wall, Lilia Sanchez, Kelly Scribner Tuttle, Scott J Pearson, Shivatheja Soma, Garhett L Wyatt, Hannah N Carter, Ramsey M Jenschke, Lin Tan, Sara A Martinez, Philip L Lorenzi, Vishal M Gohil, Monique Rijnkels, Weston W Porter.
      Dysregulation of cellular metabolism is a hallmark of breast cancer progression and is associated with metastasis and therapeutic resistance. Here, we show that the breast tumor suppressor gene SIM2 promotes mitochondrial oxidative phosphorylation (OXPHOS) using breast cancer cell line models. Mechanistically, we found that SIM2s functions not as a transcription factor but localizes to mitochondria and directly interacts with the mitochondrial respiratory chain (MRC) to facilitate functional supercomplex (SC) formation. Loss of SIM2s expression disrupts SC formation through destabilization of MRC Complex III, leading to inhibition of electron transport, although Complex I (CI) activity is retained. A metabolomic analysis showed that knockout of SIM2s leads to a compensatory increase in ATP production through glycolysis and accelerated glutamine-driven TCA cycle production of NADH, creating a favorable environment for high cell proliferation. Our findings indicate that SIM2s is a novel stabilizing factor required for SC assembly, providing insight into the impact of the MRC on metabolic adaptation and breast cancer progression.
    DOI:  https://doi.org/10.1038/s12276-023-00996-0
  6. Antioxid Redox Signal. 2023 May 03.
    Redox homeostasis and beyond: The role of wild-type Isocitrate Dehydrogenases for the pathogenesis of Glioblastoma.
    Alexander H Stegh, Craig Horbinski, Kevin Murnan.
       SIGNIFICANCE: Glioblastoma is an aggressive and devastating brain tumor characterized by a dismal prognosis and resistance to therapeutic intervention. To support catabolic processes critical for unabated cellular growth and defend against harmful reactive oxygen species, glioblastoma tumors upregulate the expression of wild-type Isocitrate Dehydrogenases (IDHs). IDH enzymes catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), NAD(P)H, and CO2. On molecular levels, IDHs epigenetically control gene expression through effects on α-KG-dependent dioxygenases, maintain redox balance, and promote anaplerosis by providing cells with NADPH and precursor substrates for macromolecular synthesis.
    RECENT ADVANCES: While gain-of-function mutations in IDH1 and IDH2 represent one of the most comprehensively studied mechanisms of IDH pathogenic effects, recent studies identified wild-type IDHs as critical regulators of normal organ physiology and, when transcriptionally induced or down-regulated, as contributing to glioblastoma progression.
    CRITICAL ISSUES: Here, we will discuss molecular mechanisms of how wild-type IDHs control glioma pathogenesis, including the regulation of oxidative stress and de novo lipid biosynthesis, and provide an overview of current and future research directives that aim to fully characterize wild-type IDH-driven metabolic reprogramming and its contribution to the pathogenesis of glioblastoma.
    FUTURE DIRECTIONS: Future studies are required to further dissect mechanisms of metabolic and epigenomic reprogramming in tumors and the tumor microenvironment, and to develop pharmacological approaches to inhibit IDH function.
    DOI:  https://doi.org/10.1089/ars.2023.0262
  7. Mol Carcinog. 2023 May 05.
    Histone deacetylase inhibitor belinostat regulates metabolic reprogramming in killing KRAS-mutant human lung cancer cells.
    Rebecca M Peter, Md Shahid Sarwar, Sarah Z Mostafa, Yujue Wang, Xiaoyang Su, Ah-Ng Kong.
      Kirsten rat sarcoma virus (KRAS) oncogene, found in 20%-25% of lung cancer patients, potentially regulates metabolic reprogramming and redox status during tumorigenesis. Histone deacetylase (HDAC) inhibitors have been investigated for treating KRAS-mutant lung cancer. In the current study, we investigate the effect of HDAC inhibitor (HDACi) belinostat at clinically relevant concentration on nuclear factor erythroid 2-related factor 2 (NRF2) and mitochondrial metabolism for the treatment of KRAS-mutant human lung cancer. LC-MS metabolomic study of belinostat on mitochondrial metabolism was performed in G12C KRAS-mutant H358 non-small cell lung cancer cells. Furthermore, l-methionine (methyl-13 C) isotope tracer was used to explore the effect of belinostat on one-carbon metabolism. Bioinformatic analyses of metabolomic data were performed to identify the pattern of significantly regulated metabolites. To study the effect of belinostat on redox signaling ARE-NRF2 pathway, luciferase reporter activity assay was done in stably transfected HepG2-C8 cells (containing pARE-TI-luciferase construct), followed by qPCR analysis of NRF2 and its target gene in H358 cells, which was further confirmed in G12S KRAS-mutant A549 cells. Metabolomic study reveals significantly altered metabolites related to redox homeostasis, including tricarboxylic acid (TCA) cycle metabolites (citrate, aconitate, fumarate, malate, and α-ketoglutarate); urea cycle metabolites (Arginine, ornithine, argino-succinate, aspartate, and fumarate); and antioxidative glutathione metabolism pathway (GSH/GSSG and NAD/NADH ratio) after belinostat treatment. 13 C stable isotope labeling data indicates potential role of belinostat in creatine biosynthesis via methylation of guanidinoacetate. Moreover, belinostat downregulated the expression of NRF2 and its target gene NAD(P)H:quinone oxidoreductase 1 (NQO1), indicating anticancer effect of belinostat is mediated, potentially via Nrf2-regulated glutathione pathway. Another HDACi panobinostat also showed potential anticancer effect in both H358 and A549 cells via Nrf2 pathway. In summary, belinostat is effective in killing KRAS-mutant human lung cancer cells by regulating mitochondrial metabolism which could be used as biomarkers for preclinical and clinical studies.
    Keywords:  HDAC inhibitor; KRAS mutation; NRF2; lung cancer; mitochondrial metabolism
    DOI:  https://doi.org/10.1002/mc.23551
  8. Nat Commun. 2023 May 02. 14(1): 2504
    Methionine restriction constrains lipoylation and activates mitochondria for nitrogenic synthesis of amino acids.
    Wen Fang, Liu Jiang, Yibing Zhu, Sen Yang, Hong Qiu, Jiou Cheng, Qingxi Liang, Zong-Cai Tu, Cunqi Ye.
      Methionine restriction (MR) provides metabolic benefits in many organisms. However, mechanisms underlying the MR-induced effect remain incompletely understood. Here, we show in the budding yeast S. cerevisiae that MR relays a signal of S-adenosylmethionine (SAM) deprivation to adapt bioenergetic mitochondria to nitrogenic anabolism. In particular, decreases in cellular SAM constrain lipoate metabolism and protein lipoylation required for the operation of the tricarboxylic acid (TCA) cycle in the mitochondria, leading to incomplete glucose oxidation with an exit of acetyl-CoA and α-ketoglutarate from the TCA cycle to the syntheses of amino acids, such as arginine and leucine. This mitochondrial response achieves a trade-off between energy metabolism and nitrogenic anabolism, which serves as an effector mechanism promoting cell survival under MR.
    DOI:  https://doi.org/10.1038/s41467-023-38289-9
  9. Crit Rev Biochem Mol Biol. 2023 Apr 26. 1-17
    The tricarboxylic acid (TCA) cycle: a malleable metabolic network to counter cellular stress.
    Alex MacLean, Felix Legendre, Vasu D Appanna.
      The tricarboxylic acid (TCA) cycle is a primordial metabolic pathway that is conserved from bacteria to humans. Although this network is often viewed primarily as an energy producing engine fueling ATP synthesis via oxidative phosphorylation, mounting evidence reveals that this metabolic hub orchestrates a wide variety of pivotal biological processes. It plays an important part in combatting cellular stress by modulating NADH/NADPH homeostasis, scavenging ROS (reactive oxygen species), producing ATP by substrate-level phosphorylation, signaling and supplying metabolites to quell a range of cellular disruptions. This review elaborates on how the reprogramming of this network prompted by such abiotic stress as metal toxicity, oxidative tension, nutrient challenge and antibiotic insult is critical for countering these conditions in mostly microbial systems. The cross-talk between the stressors and the participants of TCA cycle that results in changes in metabolite and nucleotide concentrations aimed at combatting the abiotic challenge is presented. The fine-tuning of metabolites mediated by disparate enzymes associated with this metabolic hub is discussed. The modulation of enzymatic activities aimed at generating metabolic moieties dedicated to respond to the cellular perturbation is explained. This ancient metabolic network has to be recognized for its ability to execute a plethora of physiological functions beyond its well-established traditional roles.
    Keywords:  NADH; NADPH; TCA cycle; cellular stress; keto-acids; metabolic reprogramming
    DOI:  https://doi.org/10.1080/10409238.2023.2201945
  10. Acta Pharm Sin B. 2023 Apr;13(4): 1438-1466
    The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer.
    Yang Liu, Wei Xu, Mingxue Li, Yueying Yang, Dejuan Sun, Lidian Chen, Hua Li, Lixia Chen.
      Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG). Mutants of IDH1 or IDH2 can produce d-2-hydroxyglutarate (D-2HG) with α-KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2, implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.
    Keywords:  Cancer; D-2HG; Epigenetics; IDH1; IDH1 inhibitors; Immune microenvironment; Metabolic reprogramming; Regulatory mechanisms
    DOI:  https://doi.org/10.1016/j.apsb.2022.12.019
  11. Talanta. 2023 Apr 17. pii: S0039-9140(23)00318-1. [Epub ahead of print]260 124567
    A novel GSH-activable theranostic probe containing kinase inhibitor for synergistic treatment and selective imaging of tumor cells.
    Caiyun Liu, Yan Zhang, Weimin Sun, Hanchuang Zhu, Meijun Su, Xin Wang, Xiaodi Rong, Kun Wang, Miaohui Yu, Wenlong Sheng, Baocun Zhu.
      Theranostic probe is becoming a powerful tool for diagnosis and treatment of cancer. Although some theranostic probes have been successfully developed, there is still a great room for improvement in sensitive diagnosis and efficient treatment. Herein, we developed a novel GSH-activable theranostic probe NC-G, which uses 1,8-naphthalimide-4-sulfonamide as a fluorescence imaging group and crizotinib as a highly toxic kinase inhibitor to tumor cells. The probe not only has high sensitivity (DL = 74 nM) and specificity, but also can detect GSH sensitively in cells and zebrafish. In addition, probe NC-G can not only show more obvious fluorescence in tumor cells to achieve sensitive diagnosis of tumor cells, but also release the inhibitor crizotinib to achieve high toxicity to tumor cells. It is worth noting that the consumption of GSH can cause oxidative stress response of cells and the release of SO2 can induce cell apoptosis during the recognition process of the probe and GSH. Thus, the synergistic effect of crizotinib, GSH depletion, and SO2 release provides a highly effective therapeutic feature for tumor cells. Therefore, probe NC-G can serve as an excellent theranostic probe for sensitive imaging and highly effective treatment of tumor cells.
    Keywords:  Crizotinib; Fluorescent probe; Glutathione; Kinase inhibitor; Theranostic probe
    DOI:  https://doi.org/10.1016/j.talanta.2023.124567
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:16.