bims-glucam 2022-04-03 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–04–03
twelve papers selected by
Sreeparna Banerjee, Middle East Technical University

MRI assessment of glutamine uptake correlates with the distribution of glutamine transporters and cancer stem cell markers.
Upregulation of Yin-Yang-1 Associates with Proliferation and Glutamine Metabolism in Esophageal Carcinoma.
Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth.
Pharmacological Inhibition of Glutaminase 1 Attenuates Alkali-Induced Corneal Neovascularization by Modulating Macrophages.
Maintenance of glutamine synthetase expression alleviates endotoxin-induced sepsis via alpha-ketoglutarate-mediated demethylation.
miRNA-guided reprogramming of glucose and glutamine metabolism and its impact on cell adhesion/migration during solid tumor progression.
Hypoxia Induces Saturated Fatty Acids Accumulation and Reduces Unsaturated Fatty Acids Independently of Reverse Tricarboxylic Acid Cycle in L6 Myotubes.
Glutamate blunts cell-killing effects of neutrophils in tumor microenvironment.
Carbon sources and pathways for citrate secreted by human prostate cancer cells determined by NMR tracing and metabolic modeling.
Switching to the cyclic pentose phosphate pathway powers the oxidative burst in activated neutrophils.
Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis.
Gene expression is a poor predictor of steady-state metabolite abundance in cancer cells.

Sci Rep. 2022 Apr 01. 12(1): 5511

MRI assessment of glutamine uptake correlates with the distribution of glutamine transporters and cancer stem cell markers.

Yoojeong Seo, Joyeon Kang, Tae Il Kim, Chan Gyu Joo.

Glutamine provides carbon and nitrogen for macromolecular synthesis and participates in adenosine triphosphate (ATP) generation, anabolic metabolism, redox homeostasis, cell signaling, and cancer stem cell (CSC) metabolism. New treatment strategies targeting glutamine metabolism in cancer have emerged recently. We previously reported the magnetic resonance imaging (MRI) assessment of glutamine uptake by tumors and activated glutamine metabolism in CSC. In the present study, using MRI, we determined the correlation between glutamine uptake and the distribution of glutamine transporters, namely ASCT2 and SLC38A2 (SNAT2), glutaminase (GLS), and CSC markers, such as CD44 and CD166, in a mouse xenograft model of HT29 human colorectal cancer cells. MRI data revealed an obvious change in intensity following glutamine administration. Immunohistochemistry (IHC) results indicated that ASCT2 staining was stronger in regions that exhibited high glutamine uptake (p = 0.0079). Significant differences were found in the IHC staining intensities of SNAT2, GLS, and CSC markers in the areas of high and low glutamine uptake (p = 0.0079, p = 0.0159 and p = 0.0079, respectively). We also investigated the effect of an ASCT2 inhibitor on the uptake of glutamine using MRI. A statistically significant difference in the initial glutamine uptake was found after ASCT2 inhibitor administration. To conclude, glutamine uptake is positively correlated with the distribution of ASCT2 and certain CSC markers.

DOI: https://doi.org/10.1038/s41598-022-09529-7
Int J Genomics. 2022 ;2022 9305081

Upregulation of Yin-Yang-1 Associates with Proliferation and Glutamine Metabolism in Esophageal Carcinoma.

Can Luo, Xin Chen, Yuting Bai, Lei Xu, Shuqi Wang, Lihua Yao, Xiaolan Guo, Dongsheng Wang, Xiaowu Zhong.

Objective: To investigate the expression of Yin-Yang-1 (YY1) in esophageal carcinoma (ESCA) and its effect on glutamine metabolism in ESCA.
Methods: The expression and roles of YY1 in ESCA were investigated using a series of bioinformatics databases and tools. The expression of YY1 between ESCA tissues with the corresponding adjacent tissues was validated using real-time PCR, western blot, and immunohistochemical staining method. Furthermore, the effects of YY1 on ESCC cell proliferation and migration were examined. The correlation between the YY1 and glutamine metabolism was evaluated by western blot.
Results: YY1 gene was highly conserved in evolution and upregulated in ESCA tissues and ESCC cell lines (ECA109 and TE-1). In addition, YY1 may affect the level of immune cell infiltration and promote tumor cell immune escape. Functional enrichment analysis found that YY1 involved in many biological processes, such as cell division and glutathione and glutamine metabolism. After siRNA knockdown of YY1 in ECA109 and TE-1, the proliferation and the migration of ECA109 and TE-1 were suppressed. The glutamine consumption and glutamate production were significantly decreased. The protein expression of alanine-, serine-, cysteine-preferring transporter 2 (ASCT2), glutaminase (GLS), and glutamate dehydrogenase (GLUD1) was significantly downregulated.
Conclusion: YY1 is highly expressed in ESCA and may promote glutamine metabolism of ESCC cells, indicating it may be as a diagnostic biomarker for ESCA.

DOI: https://doi.org/10.1155/2022/9305081
Sci China Life Sci. 2022 Mar 25.

Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth.

Xuan Pei, Kai-Yue Li, Yuan Shen, Jin-Tao Li, Ming-Zhu Lei, Cai-Yun Fang, Hao-Jie Lu, Hui-Juan Yang, Wenyu Wen, Miao Yin, Jia Qu, Qun-Ying Lei.

  Epithelial ovarian cancer (EOC) exhibits strong dependency on the tricarboxylic acid (TCA) cycle and oxidative phosphorylation to fuel anabolic process. Here, we show that malate dehydrogenase 2 (MDH2), a key enzyme of the TCA cycle, is palmitoylated at cysteine 138 (C138) residue, resulting in increased activity of MDH2. We next identify that ZDHHC18 acts as a palmitoyltransferase of MDH2. Glutamine deprivation enhances MDH2 palmitoylation by increasing the binding between ZDHHC18 and MDH2. MDH2 silencing represses mitochondrial respiration as well as ovarian cancer cell proliferation both in vitro and in vivo. Intriguingly, re-expression of wild-type MDH2, but not its palmitoylation-deficient C138S mutant, sustains mitochondrial respiration and restores the growth as well as clonogenic capability of ovarian cancer cells. Notably, MDH2 palmitoylation level is elevated in clinical cancer samples from patients with high-grade serous ovarian cancer. These observations suggest that MDH2 palmitoylation catalyzed by ZDHHC18 sustains mitochondrial respiration and promotes the malignancy of ovarian cancer, yielding possibilities of targeting ZDHHC18-mediated MDH2 palmitoylation in the treatment of EOC.

Keywords:  EOC; MDH2; ZDHHC18; cysteine palmitoylation; glutamine

DOI:  https://doi.org/10.1007/s11427-021-2048-2
Oxid Med Cell Longev. 2022 ;2022 1106313

Pharmacological Inhibition of Glutaminase 1 Attenuates Alkali-Induced Corneal Neovascularization by Modulating Macrophages.

Yifan Feng, Xi Yang, Jinhai Huang, Minqian Shen, Liyang Wang, Xiuping Chen, Yuanzhi Yuan, Chunqiong Dong, Xiaoping Ma, Fei Yuan.

Corneal neovascularization (CoNV) in response to chemical burns is a leading cause of vision impairment. Although glutamine metabolism plays a crucial role in macrophage polarization, its regulatory effect on macrophages involved in chemical burn-induced corneal injury is not known. Here, we elucidated the connection between the reprogramming of glutamine metabolism in macrophages and the development of alkali burn-induced CoNV. Glutaminase 1 (GLS1) expression was upregulated in the mouse corneas damaged with alkali burns and was primarily located in F4/80-positive macrophages. Treatment with a selective oral GLS1 inhibitor, CB-839 (telaglenastat), significantly decreased the distribution of polarized M2 macrophages in the alkali-injured corneas and suppressed the development of CoNV. In vitro studies further demonstrated that glutamine deprivation or CB-839 treatment inhibited the proliferation, adhesion, and M2 polarization of bone marrow-derived macrophages (BMDMs) from C57BL/6J mice. CB-839 treatment markedly attenuated the secretion of proangiogenic factors, including vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB) from interleukin-4- (IL-4-) regulated M2 macrophages. Our findings revealed that GLS1 inhibition or glutamine deprivation prevented alkali-induced CoNV by inhibiting the infiltration and M2 polarization of macrophages. This work suggests that pharmacological GLS1 inhibition is a feasible and effective treatment strategy for chemical burn-related CoNV in humans.

DOI: https://doi.org/10.1155/2022/1106313
FASEB J. 2022 May;36(5): e22281

Maintenance of glutamine synthetase expression alleviates endotoxin-induced sepsis via alpha-ketoglutarate-mediated demethylation.

Jianghong Yu, Jun Zhang, Menglin Shi, Hao Ding, Liyun Ma, Huilu Zhang, Jie Liu.

  Glutamine synthetase (Glul) is the enzyme that synthesizes endogenous glutamine, which is responsible for critical metabolic pathways and the immune system. However, the role of Glul in regulating endotoxin (lipopolysaccharide, LPS)-induced sepsis remains unclear. Here, we found that Glul expression in macrophages was significantly inhibited in endotoxemia, and that Glul deletion induced macrophages to differentiate into the pro-inflammatory type and aggravated sepsis in mice. Mechanistically, TLR4/NF-κB-induced alpha-ketoglutarate (α-KG) depletion inhibits Glul expression through H3K27me3-mediated methylation in septic mice. Both Glul overexpression with adeno-associated virus (AAV) and restoration by replenishing α-KG can alleviate the severity of sepsis. In conclusion, the study demonstrated that Glul can regulate LPS-induced sepsis and provides a novel strategy for the treatment of this disease.

Keywords:  alpha-ketoglutarate; demethylation; glutamine synthetase; macrophages; sepsis

DOI:  https://doi.org/10.1096/fj.202200059R
Cell Mol Life Sci. 2022 Mar 29. 79(4): 216

miRNA-guided reprogramming of glucose and glutamine metabolism and its impact on cell adhesion/migration during solid tumor progression.

Lorena Quirico, Francesca Orso, Stefania Cucinelli, Mladen Paradzik, Dora Natalini, Giorgia Centonze, Alberto Dalmasso, Sofia La Vecchia, Martina Coco, Valentina Audrito, Chiara Riganti, Paola Defilippi, Daniela Taverna.

  MicroRNAs (miRNAs) are small, non-coding RNAs about 22 nucleotides in length that regulate the expression of target genes post-transcriptionally, and are highly involved in cancer progression. They are able to impact a variety of cell processes such as proliferation, apoptosis and differentiation and can consequently control tumor initiation, tumor progression and metastasis formation. miRNAs can regulate, at the same time, metabolic gene expression which, in turn, influences relevant traits of malignancy such as cell adhesion, migration and invasion. Since the interaction between metabolism and adhesion or cell movement has not, to date, been well understood, in this review, we will specifically focus on miRNA alterations that can interfere with some metabolic processes leading to the modulation of cancer cell movement. In addition, we will analyze the signaling pathways connecting metabolism and adhesion/migration, alterations that often affect cancer cell dissemination and metastasis formation.

Keywords:  Adhesion; Cancer; Metabolism; Metastasis; miRNAs

DOI:  https://doi.org/10.1007/s00018-022-04228-y
Front Endocrinol (Lausanne). 2022 ;13 663625

Hypoxia Induces Saturated Fatty Acids Accumulation and Reduces Unsaturated Fatty Acids Independently of Reverse Tricarboxylic Acid Cycle in L6 Myotubes.

Lukas Vacek, Ales Dvorak, Kamila Bechynska, Vit Kosek, Moustafa Elkalaf, Minh Duc Trinh, Ivana Fiserova, Katerina Pospisilova, Lucie Slovakova, Libor Vitek, Jana Hajslova, Jan Polak.

  Obstructive sleep apnea syndrome, characterized by repetitive episodes of tissue hypoxia, is associated with several metabolic impairments. Role of fatty acids and lipids attracts attention in its pathogenesis for their metabolic effects. Parallelly, hypoxia-induced activation of reverse tricarboxylic acid cycle (rTCA) with reductive glutamine metabolism provides precursor molecules for de novo lipogenesis. Gas-permeable cultureware was used to culture L6-myotubes in chronic hypoxia (12%, 4% and 1% O2) with 13C labelled glutamine and inhibitors of glutamine uptake or rTCA-mediated lipogenesis. We investigated changes in lipidomic profile, 13C appearance in rTCA-related metabolites, gene and protein expression of rTCA-related proteins and glutamine transporters, glucose uptake and lactate production. Lipid content increased by 308% at 1% O2, predominantly composed of saturated fatty acids, while triacylglyceroles containing unsaturated fatty acids and membrane lipids (phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositol) decreased by 20-70%. rTCA labelling of malate, citrate and 2-hydroxyglutarate increased by 4.7-fold, 2.2-fold and 1.9-fold in 1% O2, respectively. ATP-dependent citrate lyase inhibition in 1% O2 decreased lipid amount by 23% and increased intensity of triacylglyceroles containing unsaturated fatty acids by 56-80%. Lactate production increased with hypoxia. Glucose uptake dropped by 75% with progression of hypoxia from 4% to 1% O2. Protein expression remained unchanged. Altogether, hypoxia modified cell metabolism leading to lipid composition alteration and rTCA activation.

Keywords:  L6 myotubes; glutamin; hypoxia; lipids; obstructive sleep apnea ; reverse TCA

DOI:  https://doi.org/10.3389/fendo.2022.663625
Cancer Sci. 2022 Apr 01.

Glutamate blunts cell-killing effects of neutrophils in tumor microenvironment.

Tiantian Xiong, Ping He, Mi Zhou, Dan Zhong, Teng Yang, Wenhui He, Zhizhen Xu, Zongtao Chen, Yang-Wuyue Liu, Shuang-Shuang Dai.

  Neutrophils are the first defenders of innate system for injury and infection. It is gradually recognized as important participants in tumor initiation and development due to heterogeneity and plasticity of neutrophils. In tumor microenvironment (TME), neutrophils might exert anti-tumor and pro-tumor functions depending on its surroundings. Tumor cells systemically alter intracellular amino acid (AA) metabolism and extracellular AA distribution to meet their proliferation need, leading to metabolic reprogramming and TME reshaping. However, the underlying mechanisms about how altered AAs affect neutrophils in TME are less-explored. Here, we identified that abundant glutamate releasing from tumor cells blunted neutrophils' cell-killing effects toward tumor cells in vitro and in vivo. Mass spectrometric detection, tumor flow and western experiments proved that increased level of pSTAT3/RAB10/ARF4 mediated by glutamate, were accompanied with immunosuppressive phenotypes of neutrophils in TME. We also discovered that Riluzole, FDA-approved glutamate release inhibitor, significantly inhibited tumor growth by restoring neutrophils' cell-killing effects though decreasing glutamate secretion from tumor cells. These findings highlight the importance of tumor-released glutamate on neutrophils transformation in TME, providing new possible cancer treatment targeting at altered glutamate metabolism.

Keywords:  Glutamate; Neutrophil; Riluzole; STAT3; Tumor microenvironment

DOI:  https://doi.org/10.1111/cas.15355
Proc Natl Acad Sci U S A. 2022 Apr 05. 119(14): e2024357119

Carbon sources and pathways for citrate secreted by human prostate cancer cells determined by NMR tracing and metabolic modeling.

Frits H A van Heijster, Vincent Breukels, Kees C F J Jansen, Jack A Schalken, Arend Heerschap.

  SignificanceThe human prostate accumulates high luminal citrate levels to serve sperm viability. There is only indirect qualitative evidence about metabolic pathways and carbon sources maintaining these levels. Human citrate-secreting prostate cancer cells were supplied with 13C-labeled substrates, and NMR spectra of extracellular fluid were recorded. We report absolute citrate production rates of prostate cells and direct evidence that glucose is the main carbon source for secreted citrate. Pyruvate carboxylase provides sufficient anaplerotic carbons to support citrate secretion. Glutamine carbons exchange with carbons for secreted citrate but are likely not involved in its net synthesis. Moreover, we developed metabolic models employing the 13C distribution in extracellular citrate as input to assess intracellular pathways followed by carbons toward citrate.

Keywords:  Krebs cycle; cancer; carbon-13; citrate; prostate

DOI:  https://doi.org/10.1073/pnas.2024357119
Nat Metab. 2022 Mar;4(3): 389-403

Switching to the cyclic pentose phosphate pathway powers the oxidative burst in activated neutrophils.

Emily C Britt, Jorgo Lika, Morgan A Giese, Taylor J Schoen, Gretchen L Seim, Zhengping Huang, Pui Y Lee, Anna Huttenlocher, Jing Fan.

Neutrophils are cells at the frontline of innate immunity that can quickly activate effector functions to eliminate pathogens upon stimulation. However, little is known about the metabolic adaptations that power these functions. Here we show rapid metabolic alterations in neutrophils upon activation, particularly drastic reconfiguration around the pentose phosphate pathway, which is specifically and quantitatively coupled to an oxidative burst. During this oxidative burst, neutrophils switch from glycolysis-dominant metabolism to a unique metabolic mode termed 'pentose cycle', where all glucose-6-phosphate is diverted into oxidative pentose phosphate pathway and net flux through upper glycolysis is reversed to allow substantial recycling of pentose phosphates. This reconfiguration maximizes NADPH yield to fuel superoxide production via NADPH oxidase. Disruptions of pentose cycle greatly suppress oxidative burst, the release of neutrophil extracellular traps and pathogen killing by neutrophils. Together, these results demonstrate the remarkable metabolic flexibility of neutrophils, which is essential for their functions as the first responders in innate immunity.

DOI: https://doi.org/10.1038/s42255-022-00550-8
Mol Metab. 2022 Mar 25. pii: S2212-8778(22)00050-3. [Epub ahead of print] 101481

Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis.

Aakriti Jain, Roberto Zoncu.

  Spatial compartmentalization of metabolic pathways within membrane-separated organelles is key to the ability of eukaryotic cells to precisely regulate their biochemical functions. Membrane-bound organelles such as mitochondria, endoplasmic reticulum (ER) and lysosomes enable the concentration of metabolic precursors within optimized chemical environments, greatly accelerating the efficiency of both anabolic and catabolic reactions, enabling division of labor and optimal utilization of resources. However, metabolic compartmentalization also poses a challenge to cells because it creates spatial discontinuities that must be bridged for reaction cascades to be connected and completed. To do so, cells employ different methods to coordinate metabolic fluxes occurring in different organelles, such as membrane-localized transporters to facilitate regulated metabolite exchange between mitochondria and lysosomes, non-vesicular transport pathways via physical contact sites connecting the ER with both mitochondria and lysosomes, as well as localized regulatory signaling processes that coordinately regulate the activity of all these organelles. Effective communication among these systems is essential to cellular health and function, whereas disruption of inter-organelle communication is an emerging driver in a multitude of diseases, from cancer to neurodegeneration.

Keywords:  Contact sites; Lysosome; Metabolism; Mitochondria; Transporters; mTORC1

DOI:  https://doi.org/10.1016/j.molmet.2022.101481
FASEB J. 2022 May;36(5): e22296

Gene expression is a poor predictor of steady-state metabolite abundance in cancer cells.

Huaping Li, Jayne A Barbour, Xiaoqiang Zhu, Jason W H Wong.

  Metabolic reprogramming is a hallmark of cancer characterized by global changes in metabolite levels. However, compared with the study of gene expression, profiling of metabolites in cancer samples remains relatively understudied. We obtained metabolomic profiling and gene expression data from 454 human solid cancer cell lines across 24 cancer types from the Cancer Cell Line Encyclopedia (CCLE) database, to evaluate the feasibility of inferring metabolite levels from gene expression data. For each metabolite, we trained multivariable LASSO regression models to identify gene sets that are most predictive of the level of each metabolite profiled. Even when accounting for cell culture conditions or cell lineage in the model, few metabolites could be accurately predicted. In some cases, the inclusion of the upstream and downstream metabolites improved prediction accuracy, suggesting that gene expression is a poor predictor of steady-state metabolite levels. Our analysis uncovered a single robust relationship between the expression of nicotinamide N-methyltransferase (NNMT) and 1-methylnicotinamide (MNA), however, this relationship could only be validated in cancer samples with high purity, as NNMT is not expressed in immune cells. Together, we have trained models that use gene expression profiles to predict the level of individual metabolites. Our analysis suggests that inferring metabolite levels based on the expression of genes is generally challenging in cancer.

Keywords:  cell line; gene expression; machine learning; metabolite; pan-cancer

DOI:  https://doi.org/10.1096/fj.202101921RR