bims-glucam 2024-07-28 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–07–28
25 papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting Cellular Adaptive Responses to Glutaminolysis Perturbation for Cancer Therapy.
Therapeutic resurgence of 6-diazo-5-oxo-l-norleucine (DON) through tissue-targeted prodrugs.
Targeting the glutamine-arginine-proline metabolism axis in cancer.
HMGA2-mediated glutamine metabolism is required for Cd-induced cell growth and cell migration.
Reprogramming of Glutamine Amino Acid Transporters Expression and Prognostic Significance in Hepatocellular Carcinoma.
Exploring the causal relationship between glutamine metabolism and leukemia risk: a Mendelian randomization and LC-MS/MS analysis.
Inhibition of glutaminolysis alone and in combination with HDAC inhibitor has anti-myeloma therapeutic effects.
100 years of the Warburg effect: A cancer metabolism endeavor.
Dietary glutamine supports mucosal germinal center B cell lymphomas.
Metastatic breast cancer cells are metabolically reprogrammed to maintain redox homeostasis during metastasis.
Glutamine metabolism in fluorosis: Integrated metabolomics and transcriptomics analysis.
Glutamine enhances pneumococcal growth under methionine semi-starvation by elevating intracellular pH.
Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells.
Oxidative Metabolism as a Cause of Lipid Peroxidation in the Execution of Ferroptosis.
Current advances in cancer energy metabolism under dietary restriction: a mini review.
Perioperative Glutamine Supplementation May Restore Atrophy of Psoas Muscles in Gastric Adenocarcinoma Patients Undergoing Gastrectomy.
The combined inhibition of SLC1A3 and glutaminase in osimertinib-resistant EGFR mutant cells.
Roles of Critical Amino Acids Metabolism in The Interactions Between Intracellular Bacterial Infection and Macrophage Function.
Microbial-derived Urolithin A targets GLS1 to inhibit glutaminolysis and attenuate cirrhotic portal hypertension.
AMPK Deficiency Increases DNA Methylation and Aggravates Colorectal Tumorigenesis in AOM/DSS Mice.
Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.
Phospholipid biosynthesis modulates nucleotide metabolism and reductive capacity.
mTOR in metabolic homeostasis and disease.
Glutathione dynamics in subcellular compartments and implications for drug development.
A Novel Amino Acid-Related Gene Signature Predicts Overall Survival in Patients With Hepatocellular Carcinoma.

Mol Cells. 2024 Jul 20. pii: S1016-8478(24)00121-3. [Epub ahead of print] 100096

Targeting Cellular Adaptive Responses to Glutaminolysis Perturbation for Cancer Therapy.

Minjoong Kim, Sunsook Hwang, Seung Min Jeong.

  Metabolic aberrations, notably deviations in glutamine metabolism, are crucial in the oncogenic process, offering vital resources for the unlimited proliferation and enhanced survival capabilities of cancer cells. The dependency of malignant cells on glutamine metabolism has led to the proposition of targeted therapeutic strategies. However, the capability of cancer cells to initiate adaptive responses undermines the efficacy of these therapeutic interventions. This review meticulously examines the multifaceted adaptive mechanisms that cancer cells deploy to sustain survival and growth following the disruption of glutamine metabolism. Emphasis is placed on the roles of transcription factors, alterations in metabolic pathways, the mTORC1 signaling axis, autophagy, macropinocytosis, nucleotide biosynthesis, and the scavenging of reactive oxygen species. Thus, the delineation and subsequent targeting of these adaptive responses in the context of therapies aimed at glutamine metabolism offer a promising avenue for circumventing drug resistance in cancer treatment.

Keywords:  adaptive response; cancer therapy; glutamine metabolism

DOI:  https://doi.org/10.1016/j.mocell.2024.100096
Adv Pharmacol. 2024 ;pii: S1054-3589(24)00014-0. [Epub ahead of print]100 157-180

Therapeutic resurgence of 6-diazo-5-oxo-l-norleucine (DON) through tissue-targeted prodrugs.

Kateřina Novotná, Lukáš Tenora, Barbara S Slusher, Rana Rais.

  The recognition that rapidly proliferating cancer cells rely heavily on glutamine for their survival and growth has renewed interest in the development of glutamine antagonists for cancer therapy. Glutamine plays a pivotal role as a carbon source for synthesizing lipids and metabolites through the TCA cycle, as well as a nitrogen source for synthesis of amino acid and nucleotides. Numerous studies have explored the significance of glutamine metabolism in cancer, providing a robust rationale for targeting this metabolic pathway in cancer treatment. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) has been explored as an anticancer therapeutic for nearly six decades. Initial investigations revealed remarkable efficacy in preclinical studies and promising outcomes in early clinical trials. However, further advancement of DON was hindered due to dose-limiting gastrointestinal (GI) toxicities as the GI system is highly dependent on glutamine for regulating growth and repair. In an effort to repurpose DON and mitigate gastrointestinal (GI) toxicity concerns, prodrug strategies were utilized. These strategies aimed to enhance the delivery of DON to specific target tissues, such as tumors and the central nervous system (CNS), while sparing DON delivery to normal tissues, particularly the GI tract. When administered at low daily doses, optimized for metabolic inhibition, these prodrugs exhibit remarkable effectiveness without inducing significant toxicity to normal tissues. This approach holds promise for overcoming past challenges associated with DON, offering an avenue for its successful utilization in cancer treatment.

Keywords:  6-Diazo-5-oxo-L-norleucine (DON); Gastrointestinal; Glutamine addiction; Glutamine antagonist; Metabolic inhibition; Prodrug

DOI:  https://doi.org/10.1016/bs.apha.2024.04.003
J Enzyme Inhib Med Chem. 2024 Dec;39(1): 2367129

Targeting the glutamine-arginine-proline metabolism axis in cancer.

Di Wang, Jiang-Jie Duan, Yu-Feng Guo, Jun-Jie Chen, Tian-Qing Chen, Jun Wang, Shi-Cang Yu.

  Metabolic abnormalities are an important feature of tumours. The glutamine-arginine-proline axis is an important node of cancer metabolism and plays a major role in amino acid metabolism. This axis also acts as a scaffold for the synthesis of other nonessential amino acids and essential metabolites. In this paper, we briefly review (1) the glutamine addiction exhibited by tumour cells with accelerated glutamine transport and metabolism; (2) the methods regulating extracellular glutamine entry, intracellular glutamine synthesis and the fate of intracellular glutamine; (3) the glutamine, proline and arginine metabolic pathways and their interaction; and (4) the research progress in tumour therapy targeting the glutamine-arginine-proline metabolic system, with a focus on summarising the therapeutic research progress of strategies targeting of one of the key enzymes of this metabolic system, P5CS (ALDH18A1). This review provides a new basis for treatments targeting the metabolic characteristics of tumours.

Keywords:  ALDH18A1; Glutamine; cancer; metabolism; proline

DOI:  https://doi.org/10.1080/14756366.2024.2367129
Toxicology. 2024 Jul 19. pii: S0300-483X(24)00180-X. [Epub ahead of print]507 153899

HMGA2-mediated glutamine metabolism is required for Cd-induced cell growth and cell migration.

Yanqiu Yang, Chunpeng Gao, Qiujuan Li, Yong Liu, Jun Cao.

  Cadmium (Cd) exposure significantly increases the risk of lung cancer. The demand for glutamine is increasing in cancers, including lung cancer. In this study, we investigated the role of glutamine metabolism in Cd-induced cell growth and migration. Firstly, we found that 2 μM Cd-treatment up-regulated the expression of ASCT2 (alanine, serine, cysteine-preferring transporter 2) and ASNS (asparagine synthetase) while downregulating mitochondrial glutaminase GLS1 in A549 cells. The same results were obtained in male BALB/c mice treated with 0.5 and 1 mg Cd/kg body weight. Subsequently, both glutamine deprivation and transfection with siASCT2 revealed that glutamine played a role in Cd-induced cell growth and migration. Furthermore, using 4-PBA (5 mM), an inhibitor of endoplasmic reticulum (ER) stress, Tm (0.1 μg/ml), an inducer of ER stress, siHMGA2, and over-expressing HMGA2 plasmids we demonstrated that ER stress/HMGA2 axis was involved in inducing ASCT2 and ASNS, while inhibiting GLS1. Additionally, the chromatin immunoprecipitation assay using an HMGA2 antibody revealed the direct binding of the HMGA2 to the promoter sequences of the ASCT2, ASNS, and GLS1 genes. Finally, dual luciferase reporter assay determined that HMGA2 increased the transcription of ASCT2 and ASNS while inhibiting the transcription of GLS1. Overall, we found that ER stress-induced HMGA2 controls glutamine metabolism by transcriptional regulation of ASCT2, ASNS and GLS1 to accelerate cell growth and migration during exposure to Cd at low concentrations. This study innovatively revealed the mechanism of Cd-induced cell growth which offers a fresh perspective on preventing Cd toxicity through glutamine metabolism.

Keywords:  Cadmium; ER stress; Glutamine metabolism; HMGA2

DOI:  https://doi.org/10.1016/j.tox.2024.153899
Int J Mol Sci. 2024 Jul 10. pii: 7558. [Epub ahead of print]25(14):

Reprogramming of Glutamine Amino Acid Transporters Expression and Prognostic Significance in Hepatocellular Carcinoma.

Vincent Tambay, Valérie-Ann Raymond, Laure Voisin, Sylvain Meloche, Marc Bilodeau.

  Hepatocellular carcinoma (HCC) is the most prevalent primary liver malignancy and is a major cause of cancer-related mortality in the world. This study aimed to characterize glutamine amino acid transporter expression profiles in HCC compared to those of normal liver cells. In vitro and in vivo models of HCC were studied using qPCR, whereas the prognostic significance of glutamine transporter expression levels within patient tumors was analyzed through RNAseq. Solute carrier (SLC) 1A5 and SLC38A2 were targeted through siRNA or gamma-p-nitroanilide (GPNA). HCC cells depended on exogenous glutamine for optimal survival and growth. Murine HCC cells showed superior glutamine uptake rate than normal hepatocytes (p < 0.0001). HCC manifested a global reprogramming of glutamine transporters compared to normal liver: SLC38A3 levels decreased, whereas SLC38A1, SLC7A6, and SLC1A5 levels increased. Also, decreased SLC6A14 and SLC38A3 levels or increased SLC38A1, SLC7A6, and SLC1A5 levels predicted worse survival outcomes (all p < 0.05). Knockdown of SLC1A5 and/or SLC38A2 expression in human Huh7 and Hep3B HCC cells, as well as GPNA-mediated inhibition, significantly decreased the uptake of glutamine; combined SLC1A5 and SLC38A2 targeting had the most considerable impact (all p < 0.05). This study revealed glutamine transporter reprogramming as a novel hallmark of HCC and that such expression profiles are clinically significant.

Keywords:  glutamine; hepatocellular carcinoma; liver; metabolic reprogramming; transporters

DOI:  https://doi.org/10.3390/ijms25147558
Front Immunol. 2024 ;15 1418738

Exploring the causal relationship between glutamine metabolism and leukemia risk: a Mendelian randomization and LC-MS/MS analysis.

Na Li, Tianyi Wang, Huiying Zhang, Xiao Li, Haochen Bai, Ning Lu, Kaizhi Lu.

   Objective: This investigation sought to delineate the causal nexus between plasma glutamine concentrations and leukemia susceptibility utilizing bidirectional Mendelian Randomization (MR) analysis and to elucidate the metabolic ramifications of asparaginase therapy on glutamine dynamics in leukemia patients.
Methods: A bidirectional two-sample MR framework was implemented, leveraging genetic variants as instrumental variables from extensive genome-wide association studies (GWAS) tailored to populations of European descent. Glutamine quantification was executed through a rigorously validated Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) protocol. Comparative analyses of glutamine levels were conducted across leukemia patients versus healthy controls, pre- and post-asparaginase administration. Statistical evaluations employed inverse variance weighted (IVW) models, MR-Egger regression, and sensitivity tests addressing pleiotropy and heterogeneity.
Results: The MR findings underscored a significant inverse association between glutamine levels and leukemia risk (IVW p = 0.03558833), positing lower glutamine levels as a contributory factor to heightened leukemia susceptibility. Conversely, the analysis disclosed no substantive causal impact of leukemia on glutamine modulation (IVW p = 0.9694758). Notably, post-asparaginase treatment, a marked decrement in plasma glutamine concentrations was observed in patients (p = 0.0068), underlining the profound metabolic influence of the therapeutic regimen.
Conclusion: This study corroborates the hypothesized inverse relationship between plasma glutamine levels and leukemia risk, enhancing our understanding of glutamine's role in leukemia pathophysiology. The pronounced reduction in glutamine levels following asparaginase intervention highlights the critical need for meticulous metabolic monitoring to refine therapeutic efficacy and optimize patient management in clinical oncology. These insights pave the way for more tailored and efficacious treatment modalities in the realm of personalized medicine.

Keywords:  LC-MS/MS; Mendelian randomization; asparaginase treatment; glutamine; leukemia; personalized medicine; therapeutic drug monitoring

DOI:  https://doi.org/10.3389/fimmu.2024.1418738
Cancer Drug Resist. 2024 ;7 25

Inhibition of glutaminolysis alone and in combination with HDAC inhibitor has anti-myeloma therapeutic effects.

Seiichi Okabe, Yuko Tanaka, Mitsuru Moriyama, Akihiko Gotoh.

  Aim: This study aimed to investigate drug candidates and their efficacy in treating refractory multiple myeloma (MM) despite significant therapeutic advances and the introduction of novel agents. Our study focused on how myeloma cells mediate the metabolic pathways essential for survival. Therefore, we examined the role of glutaminolysis in this process. Methods: We investigated the role of glutaminolysis in myeloma cell growth. In addition, we analyzed the ability of CB-839 (telaglenastat), a glutaminase (GLS) inhibitor, to suppress myeloma cell proliferation and enhance the sensitivity to histone deacetylase (HDAC) inhibitors. Results: Glutamate deprivation significantly reduced MM cell proliferation. We observed an upregulation of GLS1 expression in MM cell lines compared to that in normal controls. CB-839 inhibits MM cell proliferation in a dose-dependent manner, resulting in enhanced cytotoxicity. Additionally, intracellular α-ketoglutarate and nicotinamide adenine dinucleotide phosphate levels decreased after CB-839 administration. Combining panobinostat with CB-839 resulted in enhanced cytotoxicity and increased caspase 3/7 activity. Cells transfected with GLS shRNA exhibited reduced cell viability and elevated sub-G1 phase according to cell cycle analysis results. Compared to control cells, these cells also showed increased sensitivity to panobinostat. Conclusion: Glutaminolysis contributes to the viability of MM cells, and the GLS inhibitor CB-839 has been proven to be an effective treatment for enhancing the cytotoxic effect of HDAC inhibition. These results are clinically relevant and suggest that CB-839 is a potential therapeutic candidate for patients with MM.

Keywords:  GLS1; HDAC inhibitor; Multiple myeloma; glutaminolysis

DOI:  https://doi.org/10.20517/cdr.2024.35
Cell. 2024 Jul 25. pii: S0092-8674(24)00700-1. [Epub ahead of print]187(15): 3824-3828

100 years of the Warburg effect: A cancer metabolism endeavor.

Sarah-Maria Fendt.

If you are a scientist and you only know one thing about tumor metabolism, it's likely the Warburg effect. But who was Otto Warburg, and how did his discoveries regarding the metabolism of tumors shape our current thinking about the metabolic needs of cancer cells?

DOI: https://doi.org/10.1016/j.cell.2024.06.026
Nat Immunol. 2024 Jul 22.

Dietary glutamine supports mucosal germinal center B cell lymphomas.

DOI: https://doi.org/10.1038/s41590-024-01911-z
Redox Biol. 2024 Jul 20. pii: S2213-2317(24)00254-4. [Epub ahead of print]75 103276

Metastatic breast cancer cells are metabolically reprogrammed to maintain redox homeostasis during metastasis.

Marco Biondini, Camille Lehuédé, Sébastien Tabariès, Matthew G Annis, Alain Pacis, Eric H Ma, Christine Tam, Brian E Hsu, Yannick Audet-Delage, Afnan Abu-Thuraia, Charlotte Girondel, Valerie Sabourin, Stephanie P Totten, Mariana de Sá Tavares Russo, Gaëlle Bridon, Daina Avizonis, Marie-Christine Guiot, Julie St-Pierre, Josie Ursini-Siegel, Russell Jones, Peter M Siegel.

  Metabolic rewiring is essential for tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. We have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic program characterized by increased HIF-1α activity and dependence on glycolysis. Here, we confirm by in vivo stable isotope tracing analysis (SITA) that liver-metastatic breast cancer cells retain a glycolytic profile when grown as mammary tumors or liver metastases. However, hepatic metastases exhibit unique metabolic adaptations including elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to mammary tumors. Accordingly, breast-cancer-liver-metastases exhibited enhanced de novo GSH synthesis. Confirming their increased capacity to mitigate ROS-mediated damage, liver metastases display reduced levels of 8-Oxo-2'-deoxyguanosine. Depletion of the catalytic subunit of the rate-limiting enzyme in glutathione biosynthesis, glutamate-cysteine ligase (GCLC), strongly reduced the capacity of breast cancer cells to form liver metastases, supporting the importance of these distinct metabolic adaptations. Loss of GCLC also affected the early steps of the metastatic cascade, leading to decreased numbers of circulating tumor cells (CTCs) and impaired metastasis to the liver and the lungs. Altogether, our results indicate that GSH metabolism could be targeted to prevent the dissemination of breast cancer cells.

Keywords:  Breast cancer; GCLC; Glutathione; Glycolysis; HIF-1α; Liver metastasis; Metabolism; Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2024.103276
Sci Total Environ. 2024 Jul 23. pii: S0048-9697(24)05127-1. [Epub ahead of print] 174977

Glutamine metabolism in fluorosis: Integrated metabolomics and transcriptomics analysis.

Yue Ba, Shu Niu, Zichen Feng, Shuo Yang, Shuiyuan Yu, Chaofan Shi, Xuecheng Jiao, Guoyu Zhou, Fangfang Yu.

   OBJECTIVE: To identify the potential metabolic biomarkers of fluorosis and the pathogenesis of fluorosis.
METHODS: Sprague Dawley rats in this study were randomly divided into fluoride exposure and control groups. In the fluoride exposure group, six offspring rats without dental fluorosis were defined as group A, and six offspring rats with dental fluorosis were defined as group C. Eight offspring rats in the control group were defined as group B. The metabolites in plasma were determined using GC-MS, with differential metabolites (DMs) identified using VIP > 1, and P < 0.05. Cluster analysis, KEGG pathway enrichment analysis and Receiver Operating Characteristic (ROC) analysis were subsequently performed. The DMs which were caused by fluoride exposure in the previous study were used to verify our results. The GSE70719 from GEO database were used to support this research at the mRNA level and in vitro experiment were selected to verify above results.
RESULTS: The 13 up-regulated and 4 down-regulated DMs were identified in the group A + C, the 18 up-regulated and 4 down-regulated DMs were identified in group A, and the 12 up-regulated and 2 down-regulated DMs were identified in group C. All groups showed enrichment in Aminoacyl-tRNA synthesis, d-glutamine and D-glutamate metabolism, Nitrogen metabolism, and Purine metabolism pathways. ROC analysis revealed that l-glutamine had excellent diagnostic ability for fluorosis (AUC > 0.85, P < 0.05). Changes in major DMs (l-glutamine, 4-hydroxyproline and L-alanine) were consistent with previous findings. Transcriptomic results showed the significant alteration of GLS gene in the fluoride exposure group. In vitro experiments confirmed decreased GLS and SLC1A5 genes expression.
CONCLUSION: l-glutamine emerges as a potential biomarker for fluorosis. Glutamine metabolism was involved in the pathogenesis of fluorosis.

Keywords:  Differential metabolites; Fluorosis; l-glutamine

DOI:  https://doi.org/10.1016/j.scitotenv.2024.174977
Front Microbiol. 2024 ;15 1430038

Glutamine enhances pneumococcal growth under methionine semi-starvation by elevating intracellular pH.

Chengwang Zhang, Juncheng Liu, Xiaohui Liu, Yueyu Xu, Qingxiu Gan, Qinqian Cheng, Weiping Liu, Xiangmin Gao, Songquan Wu.

   Introduction: Bacteria frequently encounter nutrient limitation in nature. The ability of living in this nutrient shortage environment is vital for bacteria to preserve their population and important for some pathogenic bacteria to cause infectious diseases. Usually, we study how bacteria survive after nutrient depletion, a total starvation condition when bacteria almost cease growth and try to survive. However, nutrient limitation may not always lead to total starvation.
Methods: Bacterial adaptation to nutrient shortage was studied by determining bacterial growth curves, intracellular pH, intracellular amino acid contents, gene transcription, protein expression, enzyme activity, and translation and replication activities.
Results: No exogenous supply of methionine results in growth attenuation of Streptococcus pneumoniae, a human pathogen. In this paper, we refer to this inhibited growth state between ceased growth under total starvation and full-speed growth with full nutrients as semi-starvation. Similar to total starvation, methionine semi-starvation also leads to intracellular acidification. Surprisingly, it is intracellular acidification but not insufficient methionine synthesis that causes growth attenuation under methionine semi-starvation. With excessive glutamine supply in the medium, intracellular methionine level was not changed, while bacterial intracellular pH was elevated to ~ 7.6 (the optimal intracellular pH for pneumococcal growth) by glutamine deamination, and bacterial growth under semi-starvation was restored fully. Our data suggest that intracellular acidification decreases translation level and glutamine supply increases intracellular pH to restore translation level, thus restoring bacterial growth.
Discussion: This growth with intracellular pH adjustment by glutamine is a novel strategy we found for bacterial adaptation to nutrient shortage, which may provide new drug targets to inhibit growth of pathogenic bacteria under semi-starvation.

Keywords:  Streptococcus pneumoniae; glutamine; growth; intracellular pH; methionine; semi-starvation

DOI:  https://doi.org/10.3389/fmicb.2024.1430038
Mol Metab. 2024 Jul 22. pii: S2212-8778(24)00126-1. [Epub ahead of print] 101995

Tissue Inhibitor of Metalloproteinase 3 (TIMP3) mutations increase glycolytic activity and dysregulate glutamine metabolism in RPE cells.

Allison Grenell, Charandeep Singh, Monisha Raju, Alyson Wolk, Sonal Dalvi, Geeng-Fu Jang, John S Crabb, Courtney E Hershberger, Kannan V Manian, Karen Hernandez, John W Crabb, Ruchira Singh, Jianhai Du, Bela Anand-Apte.

   OBJECTIVES: Mutations in Tissue Inhibitor of Metalloproteinases 3 (TIMP3) cause Sorsby's Fundus Dystrophy (SFD), a dominantly inherited, rare form of macular degeneration that results in vision loss. TIMP3 is synthesized primarily by retinal pigment epithelial (RPE) cells, which constitute the outer blood-retinal barrier. One major function of RPE is the synthesis and transport of vital nutrients, such as glucose, to the retina. Recently, metabolic dysfunction in RPE cells has emerged as an important contributing factor in retinal degenerations. We set out to determine if RPE metabolic dysfunction was contributing to SFD pathogenesis.
METHODS: Quantitative proteomics was conducted on RPE of mice expressing the S179C variant of TIMP3, known to be causative of SFD in humans. Proteins found to be differentially expressed (P<0.05) were analyzed using statistical overrepresentation analysis to determine enriched pathways, processes, and protein classes using g:profiler and PANTHER Gene Ontology. We examined the effects of mutant TIMP3 on RPE metabolism using human ARPE-19 cells expressing mutant S179C TIMP3 and patient-derived induced pluripotent stem cell-derived RPE (iRPE) carrying the S204C TIMP3 mutation. RPE metabolism was directly probed using isotopic tracing coupled with GC/MS analysis. Steady state [U-13C6] glucose isotopic tracing was preliminarily conducted on S179C ARPE-19 followed by [U-13C6] glucose and [U-13C5] glutamine isotopic tracing in SFD iRPE cells.
RESULTS: Quantitative proteomics and enrichment analysis conducted on RPE of mice expressing mutant S179C TIMP3 identified differentially expressed proteins that were enriched for metabolism-related pathways and processes. Notably these results highlighted dysregulated glycolysis and glucose metabolism. Stable isotope tracing experiments with [U-13C6] glucose demonstrated enhanced glucose utilization and glycolytic activity in S179C TIMP3 APRE-19 cells. Similarly, [U-13C6] glucose tracing in SFD iRPE revealed increased glucose contribution to glycolysis and the TCA cycle. Additionally, [U-13C5] glutamine tracing found evidence of altered malic enzyme activity.
CONCLUSION: This study provides important information on the dysregulation of RPE glucose metabolism in SFD and implicates a potential commonality with other retinal degenerative diseases, emphasizing RPE cellular metabolism as a therapeutic target.

Keywords:  RPE; TIMP3; central carbon metabolism; isotopic tracer; retinal pigment epithelium metabolism

DOI:  https://doi.org/10.1016/j.molmet.2024.101995
Int J Mol Sci. 2024 Jul 09. pii: 7544. [Epub ahead of print]25(14):

Oxidative Metabolism as a Cause of Lipid Peroxidation in the Execution of Ferroptosis.

Junichi Fujii, Hirotaka Imai.

  Ferroptosis is a type of nonapoptotic cell death that is characteristically caused by phospholipid peroxidation promoted by radical reactions involving iron. Researchers have identified many of the protein factors that are encoded by genes that promote ferroptosis. Glutathione peroxidase 4 (GPX4) is a key enzyme that protects phospholipids from peroxidation and suppresses ferroptosis in a glutathione-dependent manner. Thus, the dysregulation of genes involved in cysteine and/or glutathione metabolism is closely associated with ferroptosis. From the perspective of cell dynamics, actively proliferating cells are more prone to ferroptosis than quiescent cells, which suggests that radical species generated during oxygen-involved metabolism are responsible for lipid peroxidation. Herein, we discuss the initial events involved in ferroptosis that dominantly occur in the process of energy metabolism, in association with cysteine deficiency. Accordingly, dysregulation of the tricarboxylic acid cycle coupled with the respiratory chain in mitochondria are the main subjects here, and this suggests that mitochondria are the likely source of both radical electrons and free iron. Since not only carbohydrates, but also amino acids, especially glutamate, are major substrates for central metabolism, dealing with nitrogen derived from amino groups also contributes to lipid peroxidation and is a subject of this discussion.

Keywords:  glycolysis; metabolic remodeling; tricarboxylic acid cycle; urea cycle

DOI:  https://doi.org/10.3390/ijms25147544
Med Oncol. 2024 Jul 26. 41(9): 209

Current advances in cancer energy metabolism under dietary restriction: a mini review.

Liuxin Yang, Yudian Shao, Tingting Gao, Ousman Bajinka, Xingxing Yuan.

  The manipulation of the energy or source of food for cancer cells has attracted significant attention in oncology research. Metabolic reprogramming of the immune system allows for a deeper understanding of cancer cell mechanisms, thereby impeding their progression. A more targeted approach is the restriction of cancer cells through dietary restriction (CR), which deprives cancer cells of the preferred energy sources within the tumor microenvironment, thereby enhancing immune cell efficacy. Although there is a plethora of CR strategies that can be employed to impede cancer progression, there is currently no comprehensive review that delineates the specific dietary restrictions that target the diverse metabolic pathways of cancer cells. This mini-review introduces amino acids as anti-cancer agents and discusses the role of dietary interventions in cancer prevention and treatment. It highlights the potential of a ketogenic diet as a therapeutic approach for cancer, elucidating its distinct mechanisms of action in tumor progression. Additionally, the potential of plant-based diets as anti-cancer agents and the role of polyphenols and vitamins in anti-cancer therapy were also discussed, along with some prospective interventions for CR as anti-tumor progression.

Keywords:  Anti-cancer; Cancer; Dietary restriction; Energy reprograming; Ketogenic diet; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12032-024-02452-z
Nutrients. 2024 Jul 17. pii: 2301. [Epub ahead of print]16(14):

Perioperative Glutamine Supplementation May Restore Atrophy of Psoas Muscles in Gastric Adenocarcinoma Patients Undergoing Gastrectomy.

Jin-Ming Wu, Hsing-Hua Tsai, Shang-Ming Tseng, Kao-Lang Liu, Ming-Tsan Lin.

   BACKGROUND: Sarcopenia, characterized by degenerative skeletal muscle loss, is increasingly linked to poor surgical outcomes. Glutamine, an immune-modulating formula, may stimulate muscle protein synthesis and inhibit degradation. We used the psoas major muscle area (PMMA) at the third lumbar vertebra, normalized for height (PMMA index), as a skeletal muscle indicator. This study investigates whether perioperative glutamine supplementation mitigates psoas muscle atrophy.
METHODS: We enrolled gastric adenocarcinoma (GA) patients undergoing gastrectomy. Computed tomography assessed the psoas muscle short axis. Muscle atrophy was estimated by changes between preoperative and three-month post-gastrectomy scans. Perioperative glutamine supplementation (PGS) comprised five-day parenteral plus one-month oral use. Propensity score matching minimized potential bias. A linear regression model predicted the association.
RESULTS: Of 516 patients analyzed (2016-2019), 100 (19.4%) received PGS. After propensity score matching, each group contained 97 cases. The PGS group showed a significantly higher median PMMA index change than the non-PGS group (0.3 vs. -0.3 cm2/m2, p = 0.004). Multivariate analysis revealed that PGS was significantly associated with increased PMMA index (coefficient = 0.60; 95% CI: 0.19-1.01; p = 0.005).
CONCLUSIONS: PGS may help restore psoas muscle atrophy in GA patients undergoing gastrectomy. The underlying mechanisms likely relate to glutamine's role in protein metabolism and immune function. Further studies are needed to elucidate these mechanisms fully.

Keywords:  cachexia; gastric cancer; glutamine; psoas muscle

DOI:  https://doi.org/10.3390/nu16142301
Biochim Biophys Acta Gen Subj. 2024 Jul 24. pii: S0304-4165(24)00118-1. [Epub ahead of print] 130675

The combined inhibition of SLC1A3 and glutaminase in osimertinib-resistant EGFR mutant cells.

Nobuaki Ochi, Noriko Miyake, Masami Takeyama, Hiromichi Yamane, Takuya Fukazawa, Yasunari Nagasaki, Tatsuyuki Kawahara, Naruhiko Ichiyama, Youko Kosaka, Ayaka Mimura, Hidekazu Nakanishi, Akio Hiraki, Katsuyuki Kiura, Nagio Takigawa.

   BACKGROUND: We investigated the unknown mechanisms of osimertinib-resistant EGFR-mutant lung cancer.
METHODS: An osimertinib-resistant cell line (PC-9/OsmR2) was established through continuous exposure to osimertinib using an EGFR exon 19 deletion (19Del) lung adenocarcinoma cell line (PC-9). EGFR 19Del (M1), L858R/T790M/C797S (M6), and L858R/C797S (M8) expression vectors were introduced into Ba/F3 cells. A second osimertinib-resistant line (M1/OsmR) was established through continuous exposure to osimertinib using M1 cells.
RESULTS: SLC1A3 had the highest mRNA expression level in PC-9/OsmR2 compared to PC-9 cells by microarray analysis and SLC1A3 was increased by flow cytometry. In PC-9/OsmR2 cells, osimertinib sensitivity was significantly increased in combination with siSLC1A3. Because SLC1A3 functions in glutamic acid transport, osimertinib with a glutaminase inhibitor (CB-839) or an SLC1A3 inhibitor (TFB-TBOA) increased the sensitivity. Also, CB-839 plus TFB-TBOA without osimertinib resulted in greater susceptibility than did CB-839 or TFB-TBOA plus osimertinib. Comprehensive metabolome analysis showed that the M1/OsmR cells had significantly more glutamine and glutamic acid than M1 cells. CB-839 plus osimertinib exerted a synergistic effect on M6 cells and an additive effect on M8 cells.
CONCLUSION: Targeting glutaminase and glutamic acid may overcome the osimertinib-resistant EGFR-mutant lung cancer.

Keywords:  EGFR; Glutamic acid; Glutamine; Lung cancer; Metabolomics; SLC1A3

DOI:  https://doi.org/10.1016/j.bbagen.2024.130675
Curr Microbiol. 2024 Jul 20. 81(9): 280

Roles of Critical Amino Acids Metabolism in The Interactions Between Intracellular Bacterial Infection and Macrophage Function.

Zuowei Zhang, Yurou Wang, Lin Xia, Ying Zhang.

Macrophages, as crucial participants in the innate immune system, respond to pathogenic challenges through their dynamic metabolic adjustments, demonstrating the intimate interplay between cellular metabolism and immune function. Bacterial infection of macrophages causes changes in macrophage metabolism, affecting both macrophage function and bacterial virulence and intracellular survival. This review explores the reprogramming of amino acid metabolism in macrophages in response to bacterial infection, with a particular focus on the influence of critical amino acids such as serine, glutamine, and arginine on the immune functions of macrophages; highlights the roles of these metabolic pathways in macrophage functions such as phagocytosis, inflammatory response, immune regulation, and pathogen clearance; reveals how pathogens exploit and manipulate the amino acid metabolism within macrophages to support their own growth and replication, thereby showcasing the intricate interplay between macrophages and pathogens. It provides a foundation for understanding the interactions between macrophages amino acid metabolism and pathogens, offering potential strategies and therapeutic targets for the development of novel anti-infection therapies.

DOI: https://doi.org/10.1007/s00284-024-03801-x
Cell Mol Gastroenterol Hepatol. 2024 Jul 20. pii: S2352-345X(24)00134-6. [Epub ahead of print] 101379

Microbial-derived Urolithin A targets GLS1 to inhibit glutaminolysis and attenuate cirrhotic portal hypertension.

Rui Li, Zhile Liu, Wensou Huang, Yongjian Guo, Chan Xie, Hongmei Wu, Jianxin Liu, Xiaoyang Hong, Xiaobin Wang, Jingjun Huang, Mingyue Cai, Zhaoxiong Guo, Licong Liang, Liteng Lin, Kangshun Zhu.

   BACKGROUND AND AIMS: Cirrhotic portal hypertension (CPH) is the leading cause of mortality in patients with cirrhosis. Over 50% patients with CPH treated with current clinical pharmacotherapy still present variceal bleeding or sometimes death owing to insufficient reduction in portal pressure. Elevated intrahepatic vascular resistance (IHVR) plays a fundamental role in increasing portal pressure. Because of its potent effect in reducing portal pressure and maintaining normal portal inflow to preserve liver function, lowering the IHVR is acknowledged as an optimal anti-CPH strategy but without clinical drugs. We aimed to investigate the protective effect of microbial-derived Urolithin A (UroA) in IHVR and CPH.
METHODS: CCl4 or BDL surgery was administered to mice to induce liver fibrosis and CPH. 16S rRNA gene sequencing was used for microbial analysis. Transcriptomics and metabolomics analyses were employed to study the host and cell responses.
RESULTS: UroA was remarkably deficient in patients with CPH and was negatively correlated with disease severity. UroA deficiency was also confirmed in CPH mice and was associated with a reduced abundance of UroA-producing bacterial strain (Lactobacillus murinus, L. murinus). Glutaminolysis of hepatic stellate cells (HSCs) was identified as a previously unrecognized target of UroA. UroA inhibited the activity of glutaminase1 to suppress glutaminolysis, which counteracted fibrogenesis and contraction of HSCs and ameliorated CPH by relieving IHVR. Supplementation with UroA or L. murinus effectively ameliorated CPH in mice.
CONCLUSIONS: We for the first time identify the deficiency of gut microbial metabolite UroA as an important cause of CPH. We demonstrate that UroA exerts an excellent anti-CPH effect by suppressing HSC glutaminolysis to lower the IHVR, which highlighted its great potential as a novel therapeutic agent for CPH.

Keywords:  Urolithin A; glutamine metabolism; gut microbiota; innovative therapy; portal hypertension

DOI:  https://doi.org/10.1016/j.jcmgh.2024.101379
Genes (Basel). 2024 Jun 25. pii: 835. [Epub ahead of print]15(7):

AMPK Deficiency Increases DNA Methylation and Aggravates Colorectal Tumorigenesis in AOM/DSS Mice.

Qi Sun, Qiyu Tian, Alejandro Bravo Iniguez, Xiaofei Sun, Hui Zhang, Jeanene Deavila, Min Du, Mei-Jun Zhu.

  The incidence of colorectal cancer (CRC) is closely linked to metabolic diseases. Accumulating evidence suggests the regulatory role of AMP-activated protein kinase (AMPK) in cancer metabolic reprogramming. In this study, wild-type and AMPK knockout mice were subjected to azoxymethane-induced and dextran sulfate sodium (AOM/DSS)-promoted colitis-associated CRC induction. A stable AMPK-deficient Caco-2 cell line was also established for the mechanistic studies. The data showed that AMPK deficiency accelerated CRC development, characterized by increased tumor number, tumor size, and hyperplasia in AOM/DSS-treated mice. The aggravated colorectal tumorigenesis resulting from AMPK ablation was associated with reduced α-ketoglutarate production and ten-eleven translocation hydroxylase 2 (TET2) transcription, correlated with the reduced mismatch repair protein mutL homolog 1 (MLH1) protein. Furthermore, in AMPK-deficient Caco-2 cells, the mRNA expression of mismatch repair and tumor suppressor genes, intracellular α-ketoglutarate, and the protein level of TET2 were also downregulated. AMPK deficiency also increased hypermethylation in the CpG islands of Mlh1 in both colonic tissues and Caco-2 cells. In conclusion, AMPK deficiency leads to reduced α-ketoglutarate concentration and elevates the suppressive epigenetic modifications of tumor suppressor genes in gut epithelial cells, thereby increasing the risk of colorectal tumorigenesis. Given the modifiable nature of AMPK activity, it holds promise as a prospective molecular target for the prevention and treatment of CRC.

Keywords:  AMPK; colorectal cancer; epigenetic modification; α-ketoglutarate

DOI:  https://doi.org/10.3390/genes15070835
Nat Commun. 2024 Jul 21. 15(1): 6152

Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.

Gloria Asantewaa, Emily T Tuttle, Nathan P Ward, Yun Pyo Kang, Yumi Kim, Madeline E Kavanagh, Nomeda Girnius, Ying Chen, Katherine Rodriguez, Fabio Hecht, Marco Zocchi, Leonid Smorodintsev-Schiller, TashJaé Q Scales, Kira Taylor, Fatemeh Alimohammadi, Renae P Duncan, Zachary R Sechrist, Diana Agostini-Vulaj, Xenia L Schafer, Hayley Chang, Zachary R Smith, Thomas N O'Connor, Sarah Whelan, Laura M Selfors, Jett Crowdis, G Kenneth Gray, Roderick T Bronson, Dirk Brenner, Alessandro Rufini, Robert T Dirksen, Aram F Hezel, Aaron R Huber, Joshua Munger, Benjamin F Cravatt, Vasilis Vasiliou, Calvin L Cole, Gina M DeNicola, Isaac S Harris.

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.

DOI: https://doi.org/10.1038/s41467-024-50454-2
Nat Chem Biol. 2024 Jul 26.

Phospholipid biosynthesis modulates nucleotide metabolism and reductive capacity.

Yibing Zhu, Xiaomeng Tong, Jingyuan Xue, Hong Qiu, Dan Zhang, Dao-Qiong Zheng, Zong-Cai Tu, Cunqi Ye.

Phospholipid and nucleotide syntheses are fundamental metabolic processes in eukaryotic organisms, with their dysregulation implicated in various disease states. Despite their importance, the interplay between these pathways remains poorly understood. Using genetic and metabolic analyses in Saccharomyces cerevisiae, we elucidate how cytidine triphosphate usage in the Kennedy pathway for phospholipid synthesis influences nucleotide metabolism and redox balance. We find that deficiencies in the Kennedy pathway limit nucleotide salvage, prompting compensatory activation of de novo nucleotide synthesis and the pentose phosphate pathway. This metabolic shift enhances the production of antioxidants such as NADPH and glutathione. Moreover, we observe that the Kennedy pathway for phospholipid synthesis is inhibited during replicative aging, indicating its role in antioxidative defense as an adaptive mechanism in aged cells. Our findings highlight the critical role of phospholipid synthesis pathway choice in the integrative regulation of nucleotide metabolism, redox balance and membrane properties for cellular defense.

DOI: https://doi.org/10.1038/s41589-024-01689-z
Exp Cell Res. 2024 Jul 22. pii: S0014-4827(24)00264-7. [Epub ahead of print] 114173

mTOR in metabolic homeostasis and disease.

Xuejia Liu, Bin Guo, Qiye Li, Jing Nie.

  The ability to maintain cellular metabolic homeostasis is critical to life, in which mTOR plays an important role. This kinase integrates upstream nutrient signals and performs essential functions in physiology and metabolism by increasing metabolism and suppressing autophagy. Thus, dysregulation of mTOR activity leads to diseases, especially metabolic diseases such as cancer, type 2 diabetes and neurological disorders. Therefore, inhibition of overactivated mTOR becomes a rational approach to treat a variety of metabolic diseases. In this review, we discuss how mTOR responds to upstream signals and how mTOR regulates metabolic processes, including protein, nucleic acid, and lipid metabolism. Furthermore, we discuss the possible causes and consequences of dysregulated mTOR signaling activity, and summarize relevant applications, such as inhibition of mTOR activity to treat these diseases. This review will advance our comprehensive knowledge of the association between mTOR and metabolic homeostasis, which has significant ramifications for human health.

Keywords:  mTOR; mTOR inhibitor; mTORC1; mTORC2; metabolic homeostasis

DOI:  https://doi.org/10.1016/j.yexcr.2024.114173
Curr Opin Chem Biol. 2024 Jul 24. pii: S1367-5931(24)00081-4. [Epub ahead of print]81 102505

Glutathione dynamics in subcellular compartments and implications for drug development.

Hanfeng Lin, Lingfei Wang, Xiqian Jiang, Jin Wang.

Glutathione (GSH) is a pivotal tripeptide antioxidant essential for maintaining cellular redox homeostasis and regulating diverse cellular processes. Subcellular compartmentalization of GSH underscores its multifaceted roles across various organelles including the cytosol, mitochondria, endoplasmic reticulum, and nucleus, each exhibiting distinct regulatory mechanisms. Perturbations in GSH dynamics contribute to pathophysiological conditions, emphasizing the clinical significance of understanding its intricate regulation. This review consolidates current knowledge on subcellular GSH dynamics, highlighting its implications in drug development, particularly in covalent drug design and antitumor strategies targeting intracellular GSH levels. Challenges and future directions in deciphering subcellular GSH dynamics are discussed, advocating for innovative methodologies to advance our comprehension and facilitate the development of precise therapeutic interventions based on GSH modulation.

DOI: https://doi.org/10.1016/j.cbpa.2024.102505
Cancer Rep (Hoboken). 2024 Jul;7(7): e2131

A Novel Amino Acid-Related Gene Signature Predicts Overall Survival in Patients With Hepatocellular Carcinoma.

Shuyi Wang, Hong Huang, Xingwang Hu, Meifang Xiao, Kaili Yang, Haiyan Bu, Yupeng Jiang, Zebing Huang.

   BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is an extremely harmful malignant tumor in the world. Since the energy metabolism and biosynthesis of HCC cells are closely related to amino acids, it is necessary to further explore the relationship between amino acid-related genes and the prognosis of HCC to achieve individualized treatment. We herein aimed to develop a prognostic model for HCC based on amino acid genes.
METHODS: In this study, RNA-sequencing data of HCC patients were downloaded from the TCGA-LIHC cohort as the training cohort and the GSE14520 cohort as the validation cohort. Amino acid-related genes were derived from the Molecular Signatures Database. Univariate Cox and Lasso regression analysis were used to construct an amino acid-related signature (AARS). The predictive value of this risk score was evaluated by Kaplan-Meier (K-M) curve, receiver operating characteristic (ROC) curve, univariate and multivariate Cox regression analysis. Gene set variation analysis (GSVA) and immune characteristics evaluation were used to explore the underlying mechanisms. Finally, a nomogram was established to help the personalized prognosis assessment of patients with HCC.
RESULTS: The AARS comprises 14 amino acid-related genes to predict overall survival (OS) in HCC patients. HCC patients were divided into AARS-high group and AARS-low group according to the AARS scores. The K-M curve, ROC curve, and univariate and multivariate Cox regression analysis verified the good prediction efficiency of the risk score. Using GSVA, we found that AARS variants were concentrated in four pathways, including cholesterol metabolism, delayed estrogen response, fatty acid metabolism, and myogenesis metabolism.
CONCLUSION: Our results suggest that the AARS as a prognostic model based on amino acid-related genes is of great value in the prediction of survival of HCC, and can help improve the individualized treatment of patients with HCC.

Keywords:  biomarkers; hepatocellular carcinoma; metabolic studies; prognosis

DOI:  https://doi.org/10.1002/cnr2.2131