bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2021–08–15
nine papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. An SLC1A5 Variant Transports Glutamine to Mitochondria in Cancer Cells.
  2. Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis.
  3. Cigarette smoke promotes oral leukoplakia via regulating glutamine metabolism and M2 polarization of macrophage.
  4. Targeting ATF4-dependent pro-survival autophagy to synergize glutaminolysis inhibition.
  5. Glucose starvation induces NADPH collapse and disulfide stress in SLC7A11high cancer cells.
  6. Regiodivergent Biocatalytic Hydroxylation of L-Glutamine Facilitated by Characterization of Non-Heme Dioxygenases from Non-Ribosomal Peptide Biosyntheses.
  7. Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming.
  8. SLC15A4 mediates M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress.
  9. Spontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters.
  1. Cancer Discov. 2020 Feb;10(2): 173
    An SLC1A5 Variant Transports Glutamine to Mitochondria in Cancer Cells.
      A variant of SLC1A5 (SLC1A5_var) fueled pancreatic cancer cells' mitochondria with glutamine.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-003
  2. Nat Commun. 2021 08 10. 12(1): 4814
    Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis.
    Clément Bodineau, Mercedes Tomé, Sarah Courtois, Ana S H Costa, Marco Sciacovelli, Benoit Rousseau, Elodie Richard, Pierre Vacher, Carlos Parejo-Pérez, Emilie Bessede, Christine Varon, Pierre Soubeyran, Christian Frezza, Piedad Del Socorro Murdoch, Victor H Villar, Raúl V Durán.
      Glutamoptosis is the induction of apoptotic cell death as a consequence of the aberrant activation of glutaminolysis and mTORC1 signaling during nutritional imbalance in proliferating cells. The role of the bioenergetic sensor AMPK during glutamoptosis is not defined yet. Here, we show that AMPK reactivation blocks both the glutamine-dependent activation of mTORC1 and glutamoptosis in vitro and in vivo. We also show that glutamine is used for asparagine synthesis and the GABA shunt to produce ATP and to inhibit AMPK, independently of glutaminolysis. Overall, our results indicate that glutamine metabolism is connected with mTORC1 activation through two parallel pathways: an acute alpha-ketoglutarate-dependent pathway; and a secondary ATP/AMPK-dependent pathway. This dual metabolic connection between glutamine and mTORC1 must be considered for the future design of therapeutic strategies to prevent cell growth in diseases such as cancer.
    DOI:  https://doi.org/10.1038/s41467-021-25079-4
  3. Int J Oral Sci. 2021 Aug 09. 13(1): 25
    Cigarette smoke promotes oral leukoplakia via regulating glutamine metabolism and M2 polarization of macrophage.
    Yanan Zhu, Shuo Zhang, Jiahui Sun, Tingting Wang, Qin Liu, Guanxi Wu, Yajie Qian, Weidong Yang, Yong Wang, Wenmei Wang.
      Oral immunosuppression caused by smoking creates a microenvironment to promote the occurrence and development of oral mucosa precancerous lesions. This study aimed to investigate the role of metabolism and macrophage polarization in cigarette-promoting oral leukoplakia. The effects of cigarette smoke extract (CSE) on macrophage polarization and metabolism were studied in vivo and in vitro. The polarity of macrophages was detected by flow cytometric analysis and qPCR. Liquid chromatography-mass spectrometry (LC-MS) was used to perform a metabolomic analysis of Raw cells stimulated with CSE. Immunofluorescence and flow cytometry were used to detect the polarity of macrophages in the condition of glutamine abundance and deficiency. Cell Counting Kit-8 (CCK-8), wound-healing assay, and Annexin V-FITC (fluorescein isothiocyanate)/PI (propidium iodide) double-staining flow cytometry were applied to detect the growth and transferability and apoptosis of Leuk-1 cells in the supernatant of Raw cells which were stimulated with CSE, glutamine abundance and deficiency. Hyperkeratosis and dysplasia of the epithelium were evident in smoking mice. M2 macrophages increased under CSE stimulation in vivo and in vitro. In total, 162 types of metabolites were detected in the CSE group. The metabolites of nicotine, glutamate, arachidic acid, and arginine changed significantly. The significant enrichment pathways were also selected, including nicotine addiction, glutamine and glutamate metabolism, and arginine biosynthesis. The results also showed that the supernatant of Raw cells stimulated by CSE could induce excessive proliferation of Leuk-1 and inhibit apoptosis. Glutamine abundance can facilitate this process. Cigarette smoke promotes oral leukoplakia via regulating glutamine metabolism and macrophage M2 polarization.
    DOI:  https://doi.org/10.1038/s41368-021-00128-2
  4. Theranostics. 2021 ;11(17): 8464-8479
    Targeting ATF4-dependent pro-survival autophagy to synergize glutaminolysis inhibition.
    Shuting Han, Liyuan Zhu, Yiran Zhu, Yuan Meng, Jiaqiu Li, Ping Song, Neelum Aziz Yousafzai, Lifeng Feng, Miaoqin Chen, Yanmei Wang, Hongchuan Jin, Xian Wang.
      As glutamine plays a central role in cancer metabolism, inhibition of glutaminolysis has become an ideal anticancer therapeutic target. However, glutaminolysis inhibition leads to activation of autophagy, which compromises its antitumor effect. Hence, we investigated the mechanism underlying glutaminolysis inhibition-induced pro-survival autophagy. Methods: High-throughput sequencing was performed on colorectal cancer (CRC) cells before and after glutaminolysis inhibition to identify differentially expressed genes. Activating transcription factor 4 (ATF4) pathway enrichment in glutaminolysis inhibited cells was identified through gene set enrichment analysis. ATF4 expression was assessed by quantitative real-time PCR (qRT-PCR) and western blotting. The function of ATF4 on mechanistic target of rapamycin (mTOR) regulation was assessed by western blotting. Luciferase reporter assays and chromatin immunoprecipitation were used to confirm the regulation of DNA damage inducible transcript 4 (DDIT4) by ATF4. mRNA half-life assays, RNA immunoprecipitation, qRT-PCR and western blotting were performed to determine the relationship between FTO alpha-ketoglutarate dependent dioxygenase (FTO), YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), and ATF4. ATF4 regulation of pro-survival autophagy was measured by tandem monomeric red fluorescent protein-green fluorescent protein fluorescence microscopy. Finally, the synergistic effect of autophagy and glutaminolysis inhibition was analyzed in an azoxymethane/dextran sodium sulfate mouse model. Results: The ATF4 pathway was activated in CRC cells upon glutaminolysis inhibition. Functionally, ATF4 transcriptionally upregulated DDIT4 to suppress mTOR, which induced pro-survival autophagy during glutaminolysis inhibition. Interestingly, glutaminolysis inhibition promoted ATF4 mRNA expression by abrogating N6-methyladenosine (m6A) modification and YTHDF2-mediated RNA decay. Finally, inhibition of ATF4-induced autophagy enhanced the antitumor efficacy of glutaminolysis inhibition. Conclusion: Glutaminolysis inhibition upregulated ATF4 expression in an m6A-dependent manner to activate pro-survival autophagy through transcriptional activation of the mTOR inhibitor DDIT4. Targeting ATF4-induced autophagy is a new strategy to synergize glutaminolysis-targeting therapies for cancer treatment.
    Keywords:  ATF4; DDIT4; Glutaminolysis inhibition; N6-methyladenosine; metabolic synthetic lethality
    DOI:  https://doi.org/10.7150/thno.60028
  5. Oncotarget. 2021 Aug 03. 12(16): 1629-1630
    Glucose starvation induces NADPH collapse and disulfide stress in SLC7A11high cancer cells.
    Xiaoguang Liu, Boyi Gan.
      
    Keywords:  NADPH; SLC7A11; cysteine; cystine; glucose starvation
    DOI:  https://doi.org/10.18632/oncotarget.27993
  6. Tetrahedron. 2021 Jun 18. pii: 132190. [Epub ahead of print]90
    Regiodivergent Biocatalytic Hydroxylation of L-Glutamine Facilitated by Characterization of Non-Heme Dioxygenases from Non-Ribosomal Peptide Biosyntheses.
    Hans Renata, Emily Shimizu, Christian R Zwick.
      We report the functional characterization of two iron- and α-ketoglutarate-dependent dioxygenases that are capable of hydroxylating free-standing glutamine at its C3 and C4 position respectively. In particular, the C4 hydroxylase, Q4Ox, catalyzes the reaction with approximately 4,300 total turnover numbers, facilitating synthesis of a solid-phase compatible building block and stereochemical elucidation at the C4 position of the hydroxylated product. This work will enable the development of novel synthetic strategies to prepare useful glutamine derivatives and stimulate further discoveries of new amino acid hydroxylases with distinct substrate specificities.
    DOI:  https://doi.org/10.1016/j.tet.2021.132190
  7. Theranostics. 2021 ;11(17): 8322-8336
    Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming.
    Zhenzhen Li, Chanjun Sun, Zhihai Qin.
      Cancer cells are well-known for adapting their metabolism to maintain high proliferation rates and survive in unfavorable environments with low oxygen and nutritional deficiency. Metabolic reprogramming most commonly arises from the tumor microenvironment (TME). The events of metabolic pathways include the Warburg effect, shift in Krebs cycle metabolites, and increase rate of oxidative phosphorylation that provides the energy for the development and invasion of cancer cells. The TME and shift in tumor metabolism shows a close relationship through bidirectional signaling pathways between the stromal and tumor cells. Cancer-associated fibroblasts (CAFs) are the main type of stromal cells in the TME and consist of a heterogeneous and plastic population that play key roles in tumor growth and metastatic capacity. Emerging evidence suggests that CAFs act as major regulators in shaping tumor metabolism especially through the dysregulation of several metabolic pathways, including glucose, amino acid, and lipid metabolism. The arrangement of these metabolic switches is believed to shape distinct CAF behavior and change tumor cell behavior by the CAFs. The crosstalk between cancer cells and CAFs is associated with cell metabolic reprogramming that contributes to cancer cell growth, progression, and evasion from cancer therapies. But the mechanism and process of this interaction remain unclear. This review aimed to highlight the metabolic couplings between tumor cells and CAFs. We reviewed the recent literature supporting an important role of CAFs in the regulation of cancer cell metabolism, and the relevant pathways, which may serve as targets for therapeutic interventions.
    Keywords:  Cancer; Cancer-associated fibroblasts; Metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.7150/thno.62378
  8. Proc Natl Acad Sci U S A. 2021 Aug 17. pii: e2100295118. [Epub ahead of print]118(33):
    SLC15A4 mediates M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress.
    Toshihiko Kobayashi, Dat Nguyen-Tien, Yuriko Sorimachi, Yuki Sugiura, Takehiro Suzuki, Hitomi Karyu, Shiho Shimabukuro-Demoto, Tatsuki Uemura, Tadashi Okamura, Tomohiko Taguchi, Kohjiro Ueki, Norihiro Kato, Nobuhito Goda, Naoshi Dohmae, Keiyo Takubo, Makoto Suematsu, Noriko Toyama-Sorimachi.
      The amino acid and oligopeptide transporter Solute carrier family 15 member A4 (SLC15A4), which resides in lysosomes and is preferentially expressed in immune cells, plays critical roles in the pathogenesis of lupus and colitis in murine models. Toll-like receptor (TLR)7/9- and nucleotide-binding oligomerization domain-containing protein 1 (NOD1)-mediated inflammatory responses require SLC15A4 function for regulating the mechanistic target of rapamycin complex 1 (mTORC1) or transporting L-Ala-γ-D-Glu-meso-diaminopimelic acid, IL-12: interleukin-12 (Tri-DAP), respectively. Here, we further investigated the mechanism of how SLC15A4 directs inflammatory responses. Proximity-dependent biotin identification revealed glycolysis as highly enriched gene ontology terms. Fluxome analyses in macrophages indicated that SLC15A4 loss causes insufficient biotransformation of pyruvate to the tricarboxylic acid cycle, while increasing glutaminolysis to the cycle. Furthermore, SLC15A4 was required for M1-prone metabolic change and inflammatory IL-12 cytokine productions after TLR9 stimulation. SLC15A4 could be in close proximity to AMP-activated protein kinase (AMPK) and mTOR, and SLC15A4 deficiency impaired TLR-mediated AMPK activation. Interestingly, SLC15A4-intact but not SLC15A4-deficient macrophages became resistant to fluctuations in environmental nutrient levels by limiting the use of the glutamine source; thus, SLC15A4 was critical for macrophage's respiratory homeostasis. Our findings reveal a mechanism of metabolic regulation in which an amino acid transporter acts as a gatekeeper that protects immune cells' ability to acquire an M1-prone metabolic phenotype in inflammatory tissues by mitigating metabolic stress.
    Keywords:  amino acid transporter; cytokine; immunometabolism; innate immune cell; macrophage
    DOI:  https://doi.org/10.1073/pnas.2100295118
  9. Nat Commun. 2021 08 12. 12(1): 4905
    Spontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters.
    Seth J Parker, Joel Encarnación-Rosado, Kate E R Hollinshead, David M Hollinshead, Leonard J Ash, Juan A K Rossi, Elaine Y Lin, Albert S W Sohn, Mark R Philips, Drew R Jones, Alec C Kimmelman.
      α-ketoglutarate (KG), also referred to as 2-oxoglutarate, is a key intermediate of cellular metabolism with pleiotropic functions. Cell-permeable esterified analogs are widely used to study how KG fuels bioenergetic and amino acid metabolism and DNA, RNA, and protein hydroxylation reactions, as cellular membranes are thought to be impermeable to KG. Here we show that esterified KG analogs rapidly hydrolyze in aqueous media, yielding KG that, in contrast to prevailing assumptions, imports into many cell lines. Esterified KG analogs exhibit spurious KG-independent effects on cellular metabolism, including extracellular acidification, arising from rapid hydrolysis and de-protonation of α-ketoesters, and significant analog-specific inhibitory effects on glycolysis or mitochondrial respiration. We observe that imported KG decarboxylates to succinate in the cytosol and contributes minimally to mitochondrial metabolism in many cell lines cultured in normal conditions. These findings demonstrate that nuclear and cytosolic KG-dependent reactions may derive KG from functionally distinct subcellular pools and sources.
    DOI:  https://doi.org/10.1038/s41467-021-25228-9
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