bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2021–04–18
eight papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Role of LncRNAs in regulating cancer amino acid metabolism.
  2. Asparagine sustains cellular proliferation and c‑Myc expression in glutamine‑starved cancer cells.
  3. CircRNA circ-OGDH (hsa_circ_0003340) Acts as a ceRNA to Regulate Glutamine Metabolism and Esophageal Squamous Cell Carcinoma Progression by the miR-615-5p/PDX1 Axis.
  4. The glycolytic process in endothelial cells and its implications.
  5. Metabolic subtypes of clear cell renal cell carcinoma defined by tobacco smoking.
  6. Kog1/Raptor mediates metabolic rewiring during nutrient limitation by controlling SNF1/AMPK activity.
  7. Loss of LUC7L2 and U1 snRNP subunits shifts energy metabolism from glycolysis to OXPHOS.
  8. The Roles of 2-Hydroxyglutarate.
  1. Cancer Cell Int. 2021 Apr 13. 21(1): 209
    Role of LncRNAs in regulating cancer amino acid metabolism.
    Yuhong Guo, Bin Lv, Renfeng Liu, Zhengzai Dai, Feifei Zhang, Yiping Liang, Bo Yu, Duo Zeng, Xiao-Bin Lv, Zhiping Zhang.
      The metabolic change of tumor cells is an extremely complicated process that involves the intersection and integration of various signal pathways. Compared with normal tissues, cancer cells show distinguished metabolic characteristics called metabolic reprogramming, which has been considered as a sign of cancer occurrence. With the deepening of tumor research in recent years, people gradually found that amino acid metabolism played crucial roles in cancer progression. Long non-coding RNAs (lncRNAs), which are implicated in many important biological processes, were firstly discovered dysregulating in cancer tissues and participating in extensive regulation of tumorigenesis. This review focuses on the reprogramming of amino acid metabolism in cancers and how lncRNAs participate in the regulatory network by interacting with other macromolecular substances. Understanding the functions of lncRNA in amino acid reprogramming in tumors might provide a new vision on the mechanisms of tumorigenesis and the development of new approaches for cancer therapy.
    Keywords:  Amino acid; Cancer; Glutamine; Metabolism; lncRNA
    DOI:  https://doi.org/10.1186/s12935-021-01926-8
  2. Oncol Rep. 2021 Jun;pii: 96. [Epub ahead of print]45(6):
    Asparagine sustains cellular proliferation and c‑Myc expression in glutamine‑starved cancer cells.
    Ilaria Chiodi, Cecilia Perini, Domenica Berardi, Chiara Mondello.
      During tumorigenesis, oncogene activation and metabolism rewiring are interconnected. Activated c‑Myc upregulates several genes involved in glutamine metabolism, making cancer cells dependent on high levels of this amino acid to survive and proliferate. After studying the response to glutamine deprivation in cancer cells, it was found that glutamine starvation not only blocked cellular proliferation, but also altered c‑Myc protein expression, leading to a reduction in the levels of the canonical c‑Myc isoform and an increase in the expression of c‑Myc 1, a c‑Myc isoform translated from an in‑frame 5' CUG codon. In an attempt to identify nutrients able to counteract glutamine deprivation effects, it was shown that, in the absence of glutamine, asparagine permitted cell survival and proliferation, and maintained c‑Myc expression as in glutamine‑fed cells, with high levels of canonical c‑Myc and c‑Myc 1 almost undetectable. In asparagine‑fed cells, global protein translation was higher than in glutamine‑starved cells, and there was an increase in the levels of glutamine synthetase (GS), whose activity was essential for cellular viability and proliferation. In glutamine‑starved asparagine‑fed cells, the inhibition of c‑Myc activity led to a decrease in global protein translation and GS synthesis, suggesting an association between c‑Myc expression, GS levels and cellular proliferation, mediated by asparagine when exogenous glutamine is absent.
    DOI:  https://doi.org/10.3892/or.2021.8047
  3. Cancer Manag Res. 2021 ;13 3041-3053
    CircRNA circ-OGDH (hsa_circ_0003340) Acts as a ceRNA to Regulate Glutamine Metabolism and Esophageal Squamous Cell Carcinoma Progression by the miR-615-5p/PDX1 Axis.
    Zongying Liang, Baoshan Zhao, Jishen Hou, Jingxiong Zheng, Guohua Xin.
       Background: Circular RNA hsa_circ_0003340 (circ-OGDH) has been uncovered to be involved in esophageal squamous cell carcinoma (ESCC) progression. However, the mechanism by which circ-OGDH regulates ESCC progression is unclear.
    Methods: Expression levels of circ-OGDH, microRNA (miR)-615-5p, and PDX1 (pancreatic and duodenal homeobox 1) mRNA were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, apoptosis, migration, invasion, and cell cycle progression of ESCC cells were analyzed by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide), colony formation, flow cytometry, and transwell assays. Measurement of glutamine consumption, α-KG (α-ketoglutarate) production, and ATP (Adenosine Triphosphate) content using corresponding kits. Protein levels were analyzed by Western blotting. The targeting relationship between circ-OGDH or PDX1 and miR-615-5p was verified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The function of circ-OGDH in ESCC was confirmed by animal experiments.
    Results: Circ-OGDH was upregulated in ESCC. Circ-OGDH inhibition reduced ESCC growth in vivo and accelerated cell apoptosis, cell cycle arrest, repressed cell proliferation, migration, invasion, and reduced cell glutamine metabolism in ESCC cells in vitro. MiR-615-5p was downregulated in ESCC, while PDX1 had an opposite result. Circ-OGDH sponged miR-615-5p to regulate PDX1 expression. MiR-615-5p inhibitor neutralized the repressive effect of circ-OGDH knockdown on malignancy and glutamine metabolism of ESCC cells. PDX1 overexpression counteracted the inhibitory impact of miR-615-5p mimic on malignancy and glutamine metabolism of ESCC cells.
    Conclusion: Circ-OGDH sponged miR-615-5p to elevate PDX1 expression, thus elevating glutamine metabolism and promoting tumor growth in ESCC. The study offered evidence to support circ-OGDH as a promising target for ESCC therapy.
    Keywords:  ESCC; PDX1; circ-OGDH; glutamine; miR-615-5p
    DOI:  https://doi.org/10.2147/CMAR.S290088
  4. Acta Pharmacol Sin. 2021 Apr 13.
    The glycolytic process in endothelial cells and its implications.
    Susan Wai Sum Leung, Yi Shi.
      Endothelial cells play an obligatory role in regulating local vascular tone and maintaining homeostasis in vascular biology. Cell metabolism, converting food to energy in organisms, is the primary self-sustaining mechanism for cell proliferation and reproduction, structure maintenance, and fight-or-flight responses to stimuli. Four major metabolic processes take place in the energy-producing process, including glycolysis, oxidative phosphorylation, glutamine metabolism, and fatty acid oxidation. Among them, glycolysis is the primary energy-producing mechanism in endothelial cells. The present review focused on glycolysis in endothelial cells under both physiological and pathological conditions. Since the switches among metabolic processes precede the functional changes and disease developments, some prophylactic and/or therapeutic strategies concerning the role of glycolysis in cardiovascular disease are discussed.
    Keywords:  cardiovascular disease; endothelial cells; glucose transporters; glycolysis; hexokinase 2; phosphofructokinase/fructose bisphosphatase 3; pyruvate kinase enzyme M2
    DOI:  https://doi.org/10.1038/s41401-021-00647-y
  5. Mol Cell Oncol. 2021 ;8(2): 1859917
    Metabolic subtypes of clear cell renal cell carcinoma defined by tobacco smoking.
    Maria F Czyzyk-Krzeska, Jarek Meller, Julio A Landero Figueroa, David R Plas, John T Cunningham.
      Tobacco smoking (TS) results in reprogramming of major metabolic pathways, including glycolysis, the citric acid (TCA) cycle, oxidative phosphorylation, and metabolism of aspartate, glutamate and glutamine in clear cell renal cell carcinoma (ccRCC). TS alters the distribution and activities of cadmium, arsenic and copper in a manner mechanistically supporting metabolic remodeling. Alterations in metabolism and metal distribution identify new actionable targets for treatment of ccRCC.
    Keywords:  Clear cell renal cell carcinoma; arsenic; copper; oxidative phosphorylation; tobacco smoking
    DOI:  https://doi.org/10.1080/23723556.2020.1859917
  6. Sci Adv. 2021 Apr;pii: eabe5544. [Epub ahead of print]7(16):
    Kog1/Raptor mediates metabolic rewiring during nutrient limitation by controlling SNF1/AMPK activity.
    Zeenat Rashida, Rajalakshmi Srinivasan, Meghana Cyanam, Sunil Laxman.
      In changing environments, cells modulate resource budgeting through distinct metabolic routes to control growth. Accordingly, the TORC1 and SNF1/AMPK pathways operate contrastingly in nutrient replete or limited environments to maintain homeostasis. The functions of TORC1 under glucose and amino acid limitation are relatively unknown. We identified a modified form of the yeast TORC1 component Kog1/Raptor, which exhibits delayed growth exclusively during glucose and amino acid limitations. Using this, we found a necessary function for Kog1 in these conditions where TORC1 kinase activity is undetectable. Metabolic flux and transcriptome analysis revealed that Kog1 controls SNF1-dependent carbon flux apportioning between glutamate/amino acid biosynthesis and gluconeogenesis. Kog1 regulates SNF1/AMPK activity and outputs and mediates a rapamycin-independent activation of the SNF1 targets Mig1 and Cat8. This enables effective glucose derepression, gluconeogenesis activation, and carbon allocation through different pathways. Therefore, Kog1 centrally regulates metabolic homeostasis and carbon utilization during nutrient limitation by managing SNF1 activity.
    DOI:  https://doi.org/10.1126/sciadv.abe5544
  7. Mol Cell. 2021 Apr 10. pii: S1097-2765(21)00143-X. [Epub ahead of print]
    Loss of LUC7L2 and U1 snRNP subunits shifts energy metabolism from glycolysis to OXPHOS.
    Alexis A Jourdain, Bridget E Begg, Eran Mick, Hardik Shah, Sarah E Calvo, Owen S Skinner, Rohit Sharma, Steven M Blue, Gene W Yeo, Christopher B Burge, Vamsi K Mootha.
      Oxidative phosphorylation (OXPHOS) and glycolysis are the two major pathways for ATP production. The reliance on each varies across tissues and cell states, and can influence susceptibility to disease. At present, the full set of molecular mechanisms governing the relative expression and balance of these two pathways is unknown. Here, we focus on genes whose loss leads to an increase in OXPHOS activity. Unexpectedly, this class of genes is enriched for components of the pre-mRNA splicing machinery, in particular for subunits of the U1 snRNP. Among them, we show that LUC7L2 represses OXPHOS and promotes glycolysis by multiple mechanisms, including (1) splicing of the glycolytic enzyme PFKM to suppress glycogen synthesis, (2) splicing of the cystine/glutamate antiporter SLC7A11 (xCT) to suppress glutamate oxidation, and (3) secondary repression of mitochondrial respiratory supercomplex formation. Our results connect LUC7L2 expression and, more generally, the U1 snRNP to cellular energy metabolism.
    Keywords:  7q-; LUC7; MDS; Tarui disease; cancer; ferroptosis; myelodysplastic syndrome; phosphofructokinase; spliceosome; system X(c)(−)
    DOI:  https://doi.org/10.1016/j.molcel.2021.02.033
  8. Front Cell Dev Biol. 2021 ;9 651317
    The Roles of 2-Hydroxyglutarate.
    Xin Du, Hai Hu.
      2-Hydroxyglutarate (2-HG) is structurally similar to α-ketoglutarate (α-KG), which is an intermediate product of the tricarboxylic acid (TCA) cycle; it can be generated by reducing the ketone group of α-KG to a hydroxyl group. The significant role that 2-HG plays has been certified in the pathophysiology of 2-hydroxyglutaric aciduria (2HGA), tumors harboring mutant isocitrate dehydrogenase 1/2 (IDH1/2mt), and in clear cell renal cell carcinoma (ccRCC). It is taken as an oncometabolite, raising much attention on its oncogenic mechanism. In recent years, 2-HG has been verified to accumulate in the context of hypoxia or acidic pH, and there are also researches confirming the vital role that 2-HG plays in the fate decision of immune cells. Therefore, 2-HG not only participates in tumorigenesis. This text will also summarize 2-HG's identities besides being an oncometabolite and will discuss their enlightenment for future research and clinical treatment.
    Keywords:  2-Hydroxyglutarate; epigenetics; immunology; isocitrate dehydrogenase; metabolism
    DOI:  https://doi.org/10.3389/fcell.2021.651317
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