bims-glucam 2021-10-24 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021–10–24
eight papers selected by
Sreeparna Banerjee, Middle East Technical University

Tumor-suppressive function of EZH2 is through inhibiting glutaminase.
Modulating glutamine metabolism to control viral immuno-inflammatory lesions.
The pro-proliferative effect of interferon-γ in breast cancer cell lines is dependent on stimulation of ASCT2-mediated glutamine cellular uptake.
Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis.
Transcriptomics and Metabolomics Integration Reveals Redox-Dependent Metabolic Rewiring in Breast Cancer Cells.
Warburg Effect, Glutamine, Succinate, Alanine, When Oxygen Matters.
Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19.
Glycogen accumulation and phase separation drives liver tumor initiation.

Cell Death Dis. 2021 Oct 20. 12(11): 975

Tumor-suppressive function of EZH2 is through inhibiting glutaminase.

Yongfeng Liu, Cheng-E Tu, Xuxue Guo, Changjie Wu, Chuncai Gu, Qiuhua Lai, Yuxin Fang, Junqi Huang, Zhizhang Wang, Aimin Li, Side Liu.

Tumors can use metabolic reprogramming to survive nutrient stress. Epigenetic regulators play a critical role in metabolic adaptation. Here we screened a sgRNA library to identify epigenetic regulators responsible for the vulnerability of colorectal cancer (CRC) cells to glucose deprivation and found that more EZH2-knockout cells survived glucose deprivation. Then, we showed that EZH2 expression was significantly downregulated in response to glucose deprivation in a glucose-sensitive CRC cell line, and EZH2-knockdown cells were more resistant to glucose deprivation. Mechanistically, EZH2 deficiency upregulated the expression of glutaminase (GLS) and promoted the production of glutamate, which in turn led to increased synthesis of intracellular glutathione (GSH) and eventually attenuated the reactive oxygen species (ROS)-mediated cell death induced by glucose deprivation. Although EZH2 functioned as an oncogene in cancer progression and EZH2 knockout abolished colorectal cancer development in a mouse model, here we revealed a mechanistic link between EZH2 and metabolic reprogramming via the direct regulation of GLS expression and observed a negative correlation between EZH2 and GLS expression in colorectal cancer tissues. These findings further confirmed the importance of heterogeneity, provided an explanation for the clinical tolerance of cancer cells to EZH2 inhibitors from the perspective of metabolism, and proposed the possibility of combining EZH2 inhibitors and glutamine metabolism inhibitors for the treatment of cancer.

DOI: https://doi.org/10.1038/s41419-021-04212-7
Cell Immunol. 2021 Oct 14. pii: S0008-8749(21)00169-6. [Epub ahead of print]370 104450

Modulating glutamine metabolism to control viral immuno-inflammatory lesions.

Deepak Sumbria, Engin Berber, Logan Miller, Barry T Rouse.

  Infection of the cornea with HSV results in an immune-inflammatory reaction orchestrated by proinflammatory T cells that is a major cause of human vision impairment. The severity of lesions can be reduced if the representation of inflammatory T cells is changed to increase the presence of T cells with regulatory function. This report shows that inhibiting glutamine metabolism using 6-Diazo-5-oxo-l-norleucine (DON) administered via intraperitoneal (IP) starting 6 days after ocular infection and continued until day 15 significantly reduced the severity of herpetic stromal keratitis lesions. The therapy resulted in reduced neutrophils, macrophages as well proinflammatory CD4 Th1 and Th17 T cells in the cornea, but had no effect on levels of regulatory T cells. A similar change in the representation of inflammatory and regulatory T cells occurred in the trigeminal ganglion (TG) the site where HSV infection establishes latency. Glutamine metabolism was shown to be required for the in-vitro optimal induction of both Th1 and Th17 T cells but not for the induction of Treg that were increased when glutamine metabolism was inhibited. Inhibiting glutamine metabolism also changed the ability of latently infected TG cells from animals previously infected with HSV to reactivate and produce infectious virus.

Keywords:  6-Diazo-5-oxo-l-norleucine; Glutamine; HSV; Immunometabolism; Inflammation control; Latency

DOI:  https://doi.org/10.1016/j.cellimm.2021.104450
Life Sci. 2021 Oct 15. pii: S0024-3205(21)01041-9. [Epub ahead of print] 120054

The pro-proliferative effect of interferon-γ in breast cancer cell lines is dependent on stimulation of ASCT2-mediated glutamine cellular uptake.

Cláudia Silva, Nelson Andrade, Ilda Rodrigues, António Carlos Ferreira, Miguel Luz Soares, Fátima Martel.

   AIMS: Type 2 diabetes mellitus (T2DM) is a risk factor for breast cancer initiation and progression. Glutamine (GLN) is a critical nutrient for cancer cells. The aim of this study was to investigate the effect of T2DM-associated compounds upon GLN uptake by breast cancer cells.
MAIN METHODS: The in vitro uptake of 3H-GLN by breast cancer (MCF-7 and MDA-MB-231) and non-tumorigenic (MCF-12A) cell lines was measured.
KEY FINDINGS: 3H-GLN uptake in the three cell lines is mainly Na+-dependent and sensitive to the ASCT2 inhibitor GPNA. IFN-γ increased total and Na+-dependent 3H-GLN uptake in the two breast cancer cell lines, and insulin increased total and Na+-dependent 3H-GLN uptake in the non-tumorigenic cell line. GPNA abolished the increase in 3H-GLN uptake promoted by these T2DM-associated compounds. ASCT2 knockdown confirmed that the increase in 3H-GLN uptake caused by IFN-γ (in breast cancer cells) and by insulin (in non-tumorigenic cells) is ASCT2-dependent. IFN-γ (in MDA-MB-231 cells) and insulin (in MCF-12A cells) increased ASCT2 transcript and protein levels. Importantly, the pro-proliferative effect of IFN-γ in breast cancer cell lines was associated with an increase in 3H-GLN uptake which was GPNA-sensitive, blocked by ASCT2 knockdown and mediated by activation of the PI3K-, STAT3- and STAT1 intracellular signalling pathways.
SIGNIFICANCE: IFN-γ and insulin possess pro-proliferative effects in breast cancer and non-cancer cell lines, respectively, which are dependent on an increase in ASCT2-mediated glutamine transport. Thus, an effective inhibition of ASCT2-mediated glutamine uptake may be a therapeutic strategy against human breast cancer in T2DM patients.

Keywords:  ASCT2; Breast cancer; GPNA; Glutamine; Interferon-γ; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1016/j.lfs.2021.120054
JCI Insight. 2021 Oct 22. pii: e142464. [Epub ahead of print]6(20):

Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis.

Akihiro Ryuge, Tomoki Kosugi, Kayaho Maeda, Ryoichi Banno, Yang Gou, Kei Zaitsu, Takanori Ito, Yuka Sato, Akiyoshi Hirayama, Shoma Tsubota, Takashi Honda, Kazuki Nakajima, Tomoya Ozaki, Kunio Kondoh, Kazuo Takahashi, Noritoshi Kato, Takuji Ishimoto, Tomoyoshi Soga, Takahiko Nakagawa, Teruhiko Koike, Hiroshi Arima, Yukio Yuzawa, Yasuhiko Minokoshi, Shoichi Maruyama, Kenji Kadomatsu.

  Monocarboxylates, such as lactate and pyruvate, are precursors for biosynthetic pathways, including those for glucose, lipids, and amino acids via the tricarboxylic acid (TCA) cycle and adjacent metabolic networks. The transportation of monocarboxylates across the cellular membrane is performed primarily by monocarboxylate transporters (MCTs), the membrane localization and stabilization of which are facilitated by the transmembrane protein basigin (BSG). Here, we demonstrate that the MCT/BSG axis sits at a crucial intersection of cellular metabolism. Abolishment of MCT1 in the plasma membrane was achieved by Bsg depletion, which led to gluconeogenesis impairment via preventing the influx of lactate and pyruvate into the cell, consequently suppressing the TCA cycle. This net anaplerosis suppression was compensated in part by the increased utilization of glycogenic amino acids (e.g., alanine and glutamine) into the TCA cycle and by activated ketogenesis through fatty acid β-oxidation. Complementary to these observations, hyperglycemia and hepatic steatosis induced by a high-fat diet were ameliorated in Bsg-deficient mice. Furthermore, Bsg deficiency significantly improved insulin resistance induced by a high-fat diet. Taken together, the plasma membrane-selective modulation of lactate and pyruvate transport through BSG inhibition could potentiate metabolic flexibility to treat metabolic diseases.

Keywords:  Diabetes; Gluconeogenesis; Hepatology; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.142464
Cancers (Basel). 2021 Oct 09. pii: 5058. [Epub ahead of print]13(20):

Transcriptomics and Metabolomics Integration Reveals Redox-Dependent Metabolic Rewiring in Breast Cancer Cells.

Marcella Bonanomi, Noemi Salmistraro, Giulia Fiscon, Federica Conte, Paola Paci, Valentina Bravatà, Giusi Irma Forte, Tatiana Volpari, Manuela Scorza, Fabrizia Mastroianni, Stefano D'Errico, Elenio Avolio, Gennaro Piccialli, Anna Maria Colangelo, Marco Vanoni, Daniela Gaglio, Lilia Alberghina.

  Rewiring glucose metabolism toward aerobic glycolysis provides cancer cells with a rapid generation of pyruvate, ATP, and NADH, while pyruvate oxidation to lactate guarantees refueling of oxidized NAD+ to sustain glycolysis. CtPB2, an NADH-dependent transcriptional co-regulator, has been proposed to work as an NADH sensor, linking metabolism to epigenetic transcriptional reprogramming. By integrating metabolomics and transcriptomics in a triple-negative human breast cancer cell line, we show that genetic and pharmacological down-regulation of CtBP2 strongly reduces cell proliferation by modulating the redox balance, nucleotide synthesis, ROS generation, and scavenging. Our data highlight the critical role of NADH in controlling the oncogene-dependent crosstalk between metabolism and the epigenetically mediated transcriptional program that sustains energetic and anabolic demands in cancer cells.

Keywords:  CtBP2; cancer metabolic rewiring; epigenetics; metabolomics integration; transcriptomics

DOI:  https://doi.org/10.3390/cancers13205058
Biology (Basel). 2021 Oct 04. pii: 1000. [Epub ahead of print]10(10):

Warburg Effect, Glutamine, Succinate, Alanine, When Oxygen Matters.

Frédéric Bouillaud, Noureddine Hammad, Laurent Schwartz.

  Cellular bioenergetics requires an intense ATP turnover that is increased further by hypermetabolic states caused by cancer growth or inflammation. Both are associated with metabolic alterations and, notably, enhancement of the Warburg effect (also known as aerobic glycolysis) of poor efficiency with regard to glucose consumption when compared to mitochondrial respiration. Therefore, beside this efficiency issue, other properties of these two pathways should be considered to explain this paradox: (1) biosynthesis, for this only indirect effect should be considered, since lactate release competes with biosynthetic pathways in the use of glucose; (2) ATP production, although inefficient, glycolysis shows other advantages when compared to mitochondrial respiration and lactate release may therefore reflect that the glycolytic flux is higher than required to feed mitochondria with pyruvate and glycolytic NADH; (3) Oxygen supply becomes critical under hypermetabolic conditions, and the ATP/O2 ratio quantifies the efficiency of oxygen use to regenerate ATP, although aerobic metabolism remains intense the participation of anaerobic metabolisms (lactic fermentation or succinate generation) could greatly increase ATP/O2 ratio; (4) time and space constraints would explain that anaerobic metabolism is required while the general metabolism appears oxidative; and (5) active repression of respiration by glycolytic intermediates, which could ensure optimization of glucose and oxygen use.

Keywords:  ATP; cancer; energy metabolism; glycolysis; inflammation; lactic fermentation; mitochondria

DOI:  https://doi.org/10.3390/biology10101000
Cell Death Differ. 2021 Oct 18.

Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19.

Toshifumi Matsuyama, Steven K Yoshinaga, Kimitaka Shibue, Tak W Mak.

SARS-CoV-2 vaccinations have greatly reduced COVID-19 cases, but we must continue to develop our understanding of the nature of the disease and its effects on human immunity. Previously, we suggested that a dysregulated STAT3 pathway following SARS-Co-2 infection ultimately leads to PAI-1 activation and cascades of pathologies. The major COVID-19-associated metabolic risks (old age, hypertension, cardiovascular diseases, diabetes, and obesity) share high PAI-1 levels and could predispose certain groups to severe COVID-19 complications. In this review article, we describe the common metabolic profile that is shared between all of these high-risk groups and COVID-19. This profile not only involves high levels of PAI-1 and STAT3 as previously described, but also includes low levels of glutamine and NAD+, coupled with overproduction of hyaluronan (HA). SARS-CoV-2 infection exacerbates this metabolic imbalance and predisposes these patients to the severe pathophysiologies of COVID-19, including the involvement of NETs (neutrophil extracellular traps) and HA overproduction in the lung. While hyperinflammation due to proinflammatory cytokine overproduction has been frequently documented, it is recently recognized that the immune response is markedly suppressed in some cases by the expansion and activity of MDSCs (myeloid-derived suppressor cells) and FoxP3+ Tregs (regulatory T cells). The metabolomics profiles of severe COVID-19 patients and patients with advanced cancer are similar, and in high-risk patients, SARS-CoV-2 infection leads to aberrant STAT3 activation, which promotes a cancer-like metabolism. We propose that glutamine deficiency and overproduced HA is the central metabolic characteristic of COVID-19 and its high-risk groups. We suggest the usage of glutamine supplementation and the repurposing of cancer drugs to prevent the development of severe COVID-19 pneumonia.

DOI: https://doi.org/10.1038/s41418-021-00892-y
Cell. 2021 Oct 18. pii: S0092-8674(21)01175-2. [Epub ahead of print]

Glycogen accumulation and phase separation drives liver tumor initiation.

Qingxu Liu, Jiaxin Li, Weiji Zhang, Chen Xiao, Shihao Zhang, Cheng Nian, Junhong Li, Dongxue Su, Lihong Chen, Qian Zhao, Hui Shao, Hao Zhao, Qinghua Chen, Yuxi Li, Jing Geng, Lixin Hong, Shuhai Lin, Qiao Wu, Xianming Deng, Rongqin Ke, Jin Ding, Randy L Johnson, Xiaolong Liu, Lanfen Chen, Dawang Zhou.

  Glucose consumption is generally increased in tumor cells to support tumor growth. Interestingly, we report that glycogen accumulation is a key initiating oncogenic event during liver malignant transformation. We found that glucose-6-phosphatase (G6PC) catalyzing the last step of glycogenolysis is frequently downregulated to augment glucose storage in pre-malignant cells. Accumulated glycogen undergoes liquid-liquid phase separation, which results in the assembly of the Laforin-Mst1/2 complex and consequently sequesters Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme-liver glycogen phosphorylase (PYGL) deficiency in both human and mice results in glycogen storage disease along with liver enlargement and tumorigenesis in a Yap-dependent manner. Consistently, elimination of glycogen accumulation abrogates liver growth and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that cancer-initiating cells adapt a glycogen storing mode, which blocks Hippo signaling through glycogen phase separation to augment tumor incidence.

Keywords:  Hippo signaling; Mst1; Mst2; cancer initiation; glycogen storage; liver cancer; phase separation

DOI:  https://doi.org/10.1016/j.cell.2021.10.001