bims-glucam 2024-03-03 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–03–03
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Progesterone inhibits endometrial cancer growth by inhibiting glutamine metabolism through ASCT2.
Silibinin suppresses glioblastoma cell growth, invasion, stemness, and glutamine metabolism by YY1/SLC1A5 pathway.
A redox-responsive prodrug for tumor-targeted glutamine restriction.
Correction: Glutamine metabolism-related genes and immunotherapy in nonspecifc orbital infammation were validated using bioinformatics and machine learning.
Metabolic rewiring and communication in cancer immunity.
Glycolysis-non-canonical glutamine dual-metabolism regulation nanodrug enhanced the phototherapy effect for pancreatic ductal adenocarcinoma treatment.
The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism.
Effectiveness of glutamine for the treatment of radiodermatitis in cancer patients: a meta-analysis of randomized controlled trials.
Metabolism-regulating non-coding RNAs in breast cancer: roles, mechanisms and clinical applications.
CircCPA4 induces ASCT2 expression to promote tumor property of non-small cell lung cancer cells in a miR-145-5p-dependent manner.
Identification of glucose-independent and reversible metabolic pathways associated with anti-proliferative effect of metformin in liver cancer cells.
Nutrient scavenging-fueled growth in pancreatic cancer depends on caveolae-mediated endocytosis under nutrient-deprived conditions.
PKM2 diverts glycolytic flux in dependence on mitochondrial one-carbon cycle.
Disrupted Tuzzerella abundance and impaired L-glutamine levels induce Treg accumulation in ovarian endometriosis: a comprehensive multi-omics analysis.
Orally Administrated Glutamate Restored EAAT1 and 3 Expression Levels Suppressed in 5-Fluorouracil-damaged Intestinal Epithelial Cells.
mTOR pathway occupies a central role in the emergence of latent cancer cells.
An Organism-Level Quantitative Flux Model of Mammalian Energy Metabolism.

Biosci Rep. 2024 Feb 28. pii: BSR20232035. [Epub ahead of print]

Progesterone inhibits endometrial cancer growth by inhibiting glutamine metabolism through ASCT2.

Jinqiu Guo, Jianhui Fan, Yaru Zhang, Mengyue Li, Zeen Jin, Yuhong Shang, Hongshuo Zhang, Ying Kong.

  Endometrial carcinoma (EC) is a common malignancy which originates from the endometrium and grows in female reproductive system. Surgeries, as current treatment for the cancer, however, cannot meet the fertility needs of young women patients. Thus, progesterone (P4) therapy is indispensable due to its effective temporary preservation of female fertility. Many cancer cells are often accompanied by changes in metabolic phenotypes, and abnormally dependent on the amino acid glutamine. However, whether P4 exerts effect on EC via glutamine metabolism is unknown. In this study, we found that P4 could inhibit glutamine metabolism in EC cells and downregulate the expression of the glutamine transporter ASCT2. This regulation of ASCT2 affects the uptake of glutamine. Furthermore, the in vivo xenograft studies showed that P4 inhibited tumor growth and the expression of key enzymes involved in glutamine metabolism. Our study demonstrated that the direct regulation of glutamine metabolism by P4 and its anticancer effect was mediated through the inhibition of ASCT2. These results provide a mechanism underlying the effects of P4 therapy on EC from the perspective of glutamine metabolism.

Keywords:  ASCT2; Endometrial carcinoma; Glutamine metabolism; Progesterone

DOI:  https://doi.org/10.1042/BSR20232035
Transl Neurosci. 2024 Jan 01. 15(1): 20220333

Silibinin suppresses glioblastoma cell growth, invasion, stemness, and glutamine metabolism by YY1/SLC1A5 pathway.

Ming Liu, Xipeng Liu, Jianxin Qiao, Bing Cao.

   Background: Silibinin has been found to inhibit glioblastoma (GBM) progression. However, the underlying molecular mechanism by which Silibinin regulates GBM process remains unclear.
Methods: GBM cell proliferation, apoptosis, invasion, and stemness are assessed by cell counting kit-8 assay, EdU assay, flow cytometry, transwell assay, and sphere formation assay. Western blot is used to measure the protein expression levels of apoptosis-related markers, solute carrier family 1 member 5 (SLC1A5), and Yin Yang-1 (YY1). Glutamine consumption, glutamate production, and α-ketoglutarate production are detected to evaluate glutamine metabolism in cells. Also, SLC1A5 and YY1 mRNA levels are examined using quantitative real-time PCR. Chromatin immunoprecipitation assay and dual-luciferase reporter assay are used to detect the interaction between YY1 and SLC1A5. Mice xenograft models are constructed to explore Silibinin roles in vivo.
Results: Silibinin inhibits GBM cell proliferation, invasion, stemness, and glutamine metabolism, while promotes apoptosis. SLC1A5 is upregulated in GBM and its expression is decreased by Silibinin. SLC1A5 overexpression abolishes the anti-tumor effect of Silibinin in GBM cells. Transcription factor YY1 binds to SLC1A5 promoter region to induce SLC1A5 expression, and the inhibition effect of YY1 knockdown on GBM cell growth, invasion, stemness, and glutamine metabolism can be reversed by SLC1A5 overexpression. In addition, Silibinin reduces GBM tumor growth by regulating YY1/SLC1A5 pathway.
Conclusion: Silibinin plays an anti-tumor role in GBM process, which may be achieved via inhibiting YY1/SLC1A5 pathway.

Keywords:  SLC1A5; Silibinin; YY1; glioblastoma

DOI:  https://doi.org/10.1515/tnsci-2022-0333
J Control Release. 2024 Feb 29. pii: S0168-3659(24)00126-3. [Epub ahead of print]368 251-264

A redox-responsive prodrug for tumor-targeted glutamine restriction.

Céline Jasmin Prange, Nadia Yasmina Ben Sayed, Bing Feng, Christine Goepfert, Daniel Ortiz Trujillo, Xile Hu, Li Tang.

  Modulating the metabolism of cancer cells, immune cells, or both is a promising strategy to potentiate cancer immunotherapy in the nutrient-competitive tumor microenvironment. Glutamine has emerged as an ideal target as cancer cells highly rely on glutamine for replenishing the tricarboxylic acid cycle in the process of aerobic glycolysis. However, non-specific glutamine restriction may induce adverse effects in unconcerned tissues and therefore glutamine inhibitors have achieved limited success in the clinic so far. Here we report the synthesis and evaluation of a redox-responsive prodrug of 6-Diazo-5-oxo-L-norleucine (redox-DON) for tumor-targeted glutamine inhibition. When applied to treat mice bearing subcutaneous CT26 mouse colon carcinoma, redox-DON exhibited equivalent antitumor efficacy but a greatly improved safety profile, particularly, in spleen and gastrointestinal tract, as compared to the state-of-the-art DON prodrug, JHU083. Furthermore, redox-DON synergized with checkpoint blockade antibodies leading to durable cures in tumor-bearing mice. Our results suggest that redox-DON is a safe and effective therapeutic for tumor-targeted glutamine inhibition showing promise for enhanced metabolic modulatory immunotherapy. The approach of reversible chemical modification may be generalized to other metabolic modulatory drugs that suffer from overt toxicity.

Keywords:  DON (6-Diazo-5-oxo-L-norleucine); Drug delivery; Glutamine inhibitor; Immune modulation; Safety; Toxicity; cancer metabolism

DOI:  https://doi.org/10.1016/j.jconrel.2024.02.031
BMC Genomics. 2024 Feb 29. 25(1): 224

Correction: Glutamine metabolism-related genes and immunotherapy in nonspecifc orbital infammation were validated using bioinformatics and machine learning.

Zixuan Wu, Na Li, Yuan Gao, Liyuan Cao, Xiaolei Yao, Qinghua Peng.

DOI: https://doi.org/10.1186/s12864-024-10105-8
Cell Chem Biol. 2024 Feb 26. pii: S2451-9456(24)00075-8. [Epub ahead of print]

Metabolic rewiring and communication in cancer immunity.

Nicole M Chapman, Hongbo Chi.

The immune system shapes tumor development and progression. Although immunotherapy has transformed cancer treatment, its overall efficacy remains limited, underscoring the need to uncover mechanisms to improve therapeutic effects. Metabolism-associated processes, including intracellular metabolic reprogramming and intercellular metabolic crosstalk, are emerging as instructive signals for anti-tumor immunity. Here, we first summarize the roles of intracellular metabolic pathways in controlling immune cell function in the tumor microenvironment. How intercellular metabolic communication regulates anti-tumor immunity, and the impact of metabolites or nutrients on signaling events, are also discussed. We then describe how targeting metabolic pathways in tumor cells or intratumoral immune cells or via nutrient-based interventions may boost cancer immunotherapies. Finally, we conclude with discussions on profiling and functional perturbation methods of metabolic activity in intratumoral immune cells, and perspectives on future directions. Uncovering the mechanisms for metabolic rewiring and communication in the tumor microenvironment may enable development of novel cancer immunotherapies.

DOI: https://doi.org/10.1016/j.chembiol.2024.02.001
J Colloid Interface Sci. 2024 Feb 20. pii: S0021-9797(24)00385-0. [Epub ahead of print]

Glycolysis-non-canonical glutamine dual-metabolism regulation nanodrug enhanced the phototherapy effect for pancreatic ductal adenocarcinoma treatment.

Jianan Qiao, Shuhui Liu, Yanfeng Huang, Xiang Zhu, Chenyang Xue, Yan Wang, Hui Xiong, Jing Yao.

  Clinical pancreatic ductal adenocarcinoma (PDAC) treatment is severely limited by lack of effective KRAS suppression strategies. To address this dilemma, a reactive oxygen species (ROS)-responsive and PDAC-targeted nanodrug named Z/B-PLS was constructed to confront KRAS through dual-blockade of its downstream PI3K/AKT/mTOR and RAF/MEK/ERK for enhanced PDAC treatment. Specifically, photosensitizer zinc phthalocyanine (ZnPc) and PI3K/mTOR inhibitor BEZ235 (BEZ) were co-loaded into PLS which was constructed by click chemistry conjugating MEK inhibitor selumetinib (SEL) to low molecular weight heparin with ROS-responsive oxalate bond. The BEZ and SEL blocked PI3K/AKT/mTOR and RAF/MEK/ERK respectively to remodel glycolysis and non-canonical glutamine metabolism. ZnPc mediated photodynamic therapy (PDT) could enhance drug release through ROS generation, further facilitating KRAS downstream dual-blockade to create treatment-promoting drug delivery-therapeutic positive feedback. Benefiting from this broad metabolic modulation cascade, the metabolic symbiosis between normoxic and hypoxic tumor cells was also cut off simultaneously and effective tumor vascular normalization effects could be achieved. As a result, PDT was dramatically promoted through glycolysis-non-canonical glutamine dual-metabolism regulation, achieving complete elimination of tumors in vivo. Above all, this study achieved effective multidimensional metabolic modulation based on integrated smart nanodrug delivery, helping overcome the therapeutic challenges posed by KRAS mutations of PDAC.

Keywords:  Integrated smart nanodrug delivery; KRAS mutational associated metabolic reprogramming; Multidimensional metabolic modulation; Pancreatic ductal adenocarcinoma; Photodynamic therapy

DOI:  https://doi.org/10.1016/j.jcis.2024.02.141
Nat Commun. 2024 Feb 29. 15(1): 1879

The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism.

Emmanuel Benichou, Bolaji Seffou, Selin Topçu, Ophélie Renoult, Véronique Lenoir, Julien Planchais, Caroline Bonner, Catherine Postic, Carina Prip-Buus, Claire Pecqueur, Sandra Guilmeau, Marie-Clotilde Alves-Guerra, Renaud Dentin.

Cancer cells integrate multiple biosynthetic demands to drive unrestricted proliferation. How these cellular processes crosstalk to fuel cancer cell growth is still not fully understood. Here, we uncover the mechanisms by which the transcription factor Carbohydrate responsive element binding protein (ChREBP) functions as an oncogene during hepatocellular carcinoma (HCC) development. Mechanistically, ChREBP triggers the expression of the PI3K regulatory subunit p85α, to sustain the activity of the pro-oncogenic PI3K/AKT signaling pathway in HCC. In parallel, increased ChREBP activity reroutes glucose and glutamine metabolic fluxes into fatty acid and nucleic acid synthesis to support PI3K/AKT-mediated HCC growth. Thus, HCC cells have a ChREBP-driven circuitry that ensures balanced coordination between PI3K/AKT signaling and appropriate cell anabolism to support HCC development. Finally, pharmacological inhibition of ChREBP by SBI-993 significantly suppresses in vivo HCC tumor growth. Overall, we show that targeting ChREBP with specific inhibitors provides an attractive therapeutic window for HCC treatment.

DOI: https://doi.org/10.1038/s41467-024-45548-w
Support Care Cancer. 2024 Mar 01. 32(3): 201

Effectiveness of glutamine for the treatment of radiodermatitis in cancer patients: a meta-analysis of randomized controlled trials.

Hsu-Chieh Chang, Wen-Yen Huang, Po-Huang Chen, Tsai-Wei Huang, Made Satya Nugraha Gautama.

   BACKGROUND: After receiving radiation therapy, 60%-95% of patients with cancer develop radiodermatitis, which causes pain, wound infection, and poor quality of life. Glutamine is a popular nutritional supplement for patients with cancer. Several studies examined the usefulness of glutamine for reducing radiodermatitis. However, there is still no consolidated evidence for clinical use.
METHODS: We searched PubMed, Embase, Cochrane Library, CINAHL PLUS, and the China Knowledge Resource Integrated Database for the relevant literature published up to March 2023, without language restrictions. Two reviewers screened, filtered, and appraised these articles independently, and their data were pooled using a random-effects model.
RESULTS: Five randomized controlled trials (RCTs) with 218 participants were analyzed. The incidence of radiodermatitis in the glutamine group (89/110) was significantly lower than in the placebo group (99/108; risk ratio [RR], 0.90; 95% CI, 0.81-1.00; p = 0.05; I2 = 7%). The incidence of moderate to severe radiodermatitis was significantly lower in the glutamine group than in the placebo group (RR, 0.49; 95% CI, 0.32-0.76; p = 0.001; I2 = 52%). Moreover, subgroup analysis demonstrated heterogeneity (I2 = 52%) for moderate to severe radiodermatitis, the risk of which might be significantly reduced by a glutamine dose of 20-30 g/day (RR, 0.60; 95% CI, 0.41-0.87; I2 = 0%).
CONCLUSION: The meta-analysis indicate that glutamine might lead to a lower incidence of radiodermatitis, and that a glutamine dose of 20-30 g/day might decrease the incidence of moderate to severe dermatitis. Thus, the serious impact of radiodermatitis on treatment follow-up makes the clinical use of glutamine even more important. PROSPERO number: CRD42021254394.

Keywords:  Cancer; Glutamine; Meta-analysis; Radiodermatitis; Radiotherapy

DOI:  https://doi.org/10.1007/s00520-024-08411-8
J Biomed Sci. 2024 Feb 26. 31(1): 25

Metabolism-regulating non-coding RNAs in breast cancer: roles, mechanisms and clinical applications.

Shiliang Xu, Lingxia Wang, Yuexin Zhao, Tong Mo, Bo Wang, Jun Lin, Huan Yang.

  Breast cancer is one of the most common malignancies that pose a serious threat to women's health. Reprogramming of energy metabolism is a major feature of the malignant transformation of breast cancer. Compared to normal cells, tumor cells reprogram metabolic processes more efficiently, converting nutrient supplies into glucose, amino acid and lipid required for malignant proliferation and progression. Non-coding RNAs(ncRNAs) are a class of functional RNA molecules that are not translated into proteins but regulate the expression of target genes. NcRNAs have been demonstrated to be involved in various aspects of energy metabolism, including glycolysis, glutaminolysis, and fatty acid synthesis. This review focuses on the metabolic regulatory mechanisms and clinical applications of metabolism-regulating ncRNAs involved in breast cancer. We summarize the vital roles played by metabolism-regulating ncRNAs for endocrine therapy, targeted therapy, chemotherapy, immunotherapy, and radiotherapy resistance in breast cancer, as well as their potential as therapeutic targets and biomarkers. Difficulties and perspectives of current targeted metabolism and non-coding RNA therapeutic strategies are discussed.

Keywords:  Amino acid metabolism; Breast cancer; Glycolysis; Lipid metabolism; Metabolism; Non-coding RNAs

DOI:  https://doi.org/10.1186/s12929-024-01013-w
Thorac Cancer. 2024 Feb 24.

CircCPA4 induces ASCT2 expression to promote tumor property of non-small cell lung cancer cells in a miR-145-5p-dependent manner.

Zhenhua Zhang, Weiliang Liu, Tao Huang, Junyan Li, Hui Hu, Xinyu Xu, Zhigang Fan.

   BACKGROUND: Non-small cell lung cancer (NSCLC) is a type of lung cancer that occurs in the cells of the respiratory tract, and its development is influenced by the regulation of circular RNAs (circRNAs). However, the role of circRNA carboxypeptidase A4 (circCPA4) in the progression of NSCLC and the underlying mechanism remain relatively clear.
METHODS: The study utilized both real-time quantitative polymerase chain reaction (RT-qPCR) and western blot techniques to evaluate the levels of circCPA4, microRNA-145-5p (miR-145-5p), alanine, serine, or cysteine-preferring transporter 2 (ASCT2). To assess cell proliferation, cell counting kit-8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were performed. Apoptosis was determined using flow cytometry, while cell migration and invasive capacity were evaluated through transwell and wound-healing assays. Intracellular levels of glutamine, glutamate, and α-KG were measured using specific kits. The relationship between miR-145-5p and circCPA4 or ASCT2 was confirmed using dual-luciferase reporter assay and RNA immunoprecipitation assay.
RESULTS: CircCPA4 and ASCT2 RNA levels were elevated, while miR-145-5p was downregulated in both NSCLC tissues and cells. Depletion of circCPA4 significantly inhibited NSCLC cell proliferation, migration, invasion, and intracellular levels of glutamine, glutamate, and α-KG, and promoted apoptosis. Moreover, circCPA4 knockdown delayed tumor growth in vivo. Furthermore, circCPA4 was found to bind to miR-145-5p, thereby regulating the progression of NSCLC in vitro. ASCT2 was also identified as a downstream target of miR-145-5p, and its upregulation rescued the effects of miR-145-5p overexpression on NSCLC cell processes.
CONCLUSION: CircCPA4 knockdown inhibited tumor property of NSCLC cells by modulating the miR-145-5p/ASCT2 axis.

Keywords:  ASCT2; circCPA4; miR-145-5p; non-small cell lung cancer

DOI:  https://doi.org/10.1111/1759-7714.15257
Metabolomics. 2024 Feb 27. 20(2): 29

Identification of glucose-independent and reversible metabolic pathways associated with anti-proliferative effect of metformin in liver cancer cells.

Sk Ramiz Islam, Soumen Kanti Manna.

   INTRODUCTION: Despite the ability of cancer cells to survive glucose deprivation, most studies on anti-cancer effect of metformin explored its impact on glucose metabolism. No study ever examined whether its anti-cancer effect is reversible. Existing evidences warrant understanding of glucose-independent non-cytotoxic anti-proliferative effect of metformin to rationalize its role in liver cancer.
OBJECTIVES: Characterization of glucose-independent anti-proliferative metabolic effects of metformin as well as analysis of their reversibility in liver cancer cells.
METHODOLOGY: The dose-dependent effects of metformin on HepG2 cells were examined in presence and absence of glucose. The longitudinal evolution of metabolome was analyzed along with gene and protein expression as well as their correlations with and reversibility of cellular phenotype and metabolic signatures.
RESULTS: Metformin concentrations up to 2.5 mM were found to be anti-proliferative irrespective of presence of glucose without significant increase in cytotoxicity. Apart from mitochondrial impairment, derangement of fatty acid desaturation, one-carbon, glutathione, and polyamine metabolism were associated with metformin treatment irrespective of glucose supplementation. Depletion of pantothenic acid, downregulation of essential amino acid uptake and metabolism alongside purine salvage were identified as novel glucose-independent effects of metformin. These were significantly correlated with cMyc expression and reduction in proliferation. Rescue experiments established reversibility upon metformin withdrawal and tight association between proliferation, metabotype, and cMyc expression.
CONCLUSIONS: The derangement of multiple glucose-independent metabolic pathways, which are often upregulated in therapy-resistant cancer, and concomitant cMyc downregulation coordinately contribute to the anti-proliferative effect of metformin in liver cancer cells. These are reversible and may influence its therapeutic utility.

Keywords:  Glucose-independent pathways; Liver cancer; Metformin; Proliferation; cMyc

DOI:  https://doi.org/10.1007/s11306-024-02096-0
Sci Adv. 2024 Mar;10(9): eadj3551

Nutrient scavenging-fueled growth in pancreatic cancer depends on caveolae-mediated endocytosis under nutrient-deprived conditions.

Adam R Wolfe, Tiantian Cui, Sooin Baie, Sergio Corrales-Guerrero, Amy Webb, Veronica Castro-Aceituno, Duan-Liang Shyu, Joanna M Karasinska, James T Topham, Daniel J Renouf, David F Schaeffer, Megan Halloran, Rebecca Packard, Ryan Robb, Wei Chen, Nicholas Denko, Michael Lisanti, Timothy C Thompson, Philippe Frank, Terence M Williams.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its nutrient-scavenging ability, crucial for tumor progression. Here, we investigated the roles of caveolae-mediated endocytosis (CME) in PDAC progression. Analysis of patient data across diverse datasets revealed a strong association of high caveolin-1 (Cav-1) expression with higher histologic grade, the most aggressive PDAC molecular subtypes, and worse clinical outcomes. Cav-1 loss markedly promoted longer overall and tumor-free survival in a genetically engineered mouse model. Cav-1-deficient tumor cell lines exhibited significantly reduced proliferation, particularly under low nutrient conditions. Supplementing cells with albumin rescued the growth of Cav-1-proficient PDAC cells, but not in Cav-1-deficient PDAC cells under low glutamine conditions. In addition, Cav-1 depletion led to significant metabolic defects, including decreased glycolytic and mitochondrial metabolism, and downstream protein translation signaling pathways. These findings highlight the crucial role of Cav-1 and CME in fueling pancreatic tumorigenesis, sustaining tumor growth, and promoting survival through nutrient scavenging.

DOI: https://doi.org/10.1126/sciadv.adj3551
Cell Rep. 2024 Feb 28. pii: S2211-1247(24)00196-7. [Epub ahead of print]43(3): 113868

PKM2 diverts glycolytic flux in dependence on mitochondrial one-carbon cycle.

Mohaned Benzarti, Laura Neises, Anais Oudin, Christina Krötz, Elodie Viry, Ernesto Gargiulo, Coralie Pulido, Maryse Schmoetten, Vitaly Pozdeev, Nadia I Lorenz, Michael W Ronellenfitsch, David Sumpton, Marc Warmoes, Christian Jaeger, Antoine Lesur, Björn Becker, Etienne Moussay, Jerome Paggetti, Simone P Niclou, Elisabeth Letellier, Johannes Meiser.

  Modeling tumor metabolism in vitro remains challenging. Here, we used galactose as an in vitro tool compound to mimic glycolytic limitation. In contrast to the established idea that high glycolytic flux reduces pyruvate kinase isozyme M2 (PKM2) activity to support anabolic processes, we have discovered that glycolytic limitation also affects PKM2 activity. Surprisingly, despite limited carbon availability and energetic stress, cells induce a near-complete block of PKM2 to divert carbons toward serine metabolism. Simultaneously, TCA cycle flux is sustained, and oxygen consumption is increased, supported by glutamine. Glutamine not only supports TCA cycle flux but also serine synthesis via distinct mechanisms that are directed through PKM2 inhibition. Finally, deleting mitochondrial one-carbon (1C) cycle reversed the PKM2 block, suggesting a potential formate-dependent crosstalk that coordinates mitochondrial 1C flux and cytosolic glycolysis to support cell survival and proliferation during nutrient-scarce conditions.

Keywords:  CP: Cancer; CP: Metabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.113868
Metabolomics. 2024 Feb 29. 20(2): 32

Disrupted Tuzzerella abundance and impaired L-glutamine levels induce Treg accumulation in ovarian endometriosis: a comprehensive multi-omics analysis.

Yichen Chen, Lingfang Ye, Jue Zhu, Liang Chen, Huan Chen, Yuhui Sun, Yishen Rong, Jing Zhang.

   INTRODUCTION: The microbial community plays a crucial role in the pathological microenvironment. However, the structure of the microbial community within endometriotic lesions and its impact on the microenvironment is still limited.
METHODS: All 55 tissue samples, including ovarian ectopic (OEMs) and normal (NE) endometrium, were subjected to 16S rRNA sequencing, metabolomic and proteomic analysis.
RESULTS: We found the abundance of Tuzzerella is significantly lower in OEMs compared to NE tissue (p < 0.01). We selected samples from these two groups that exhibited the most pronounced difference in Tuzzerella abundance for further metabolomic and proteomic analysis. Our findings indicated that endometriotic lesions were associated with a decrease in L-Glutamine levels. However, proteomic analysis revealed a significant upregulation of proteins related to the complement pathway, including C3, C7, C1S, CLU, and A2M. Subsequent metabolic and protein correlation predictions demonstrated a negative regulation between L-Glutamine and C7. In vitro experiments further confirmed that high concentrations of Glutamine significantly inhibit C7 protein expression. Additionally, immune cell infiltration analysis, multiplex immunofluorescence, and multifactorial testing demonstrated a positive correlation between C7 expression and the infiltration of regulatory T cells (Tregs) in ectopic lesions, while L-Glutamine was found to negatively regulate the expression of chemotactic factors for Tregs.
CONCLUSION: In this study, we found a clear multi-omics pathway alteration, "Tuzzerella (microbe)-L-Glutamine (metabolite)-C7 (protein)," which affects the infiltration of Tregs in endometriotic lesions. Our findings provide insights into endometriosis classification and personalized treatment strategies based on microbial structures.

Keywords:  Endometriosis; Immune infiltration; Metabolomics; Microbiome; Proteomics

DOI:  https://doi.org/10.1007/s11306-023-02072-0
Anticancer Res. 2024 Mar;44(3): 1143-1147

Orally Administrated Glutamate Restored EAAT1 and 3 Expression Levels Suppressed in 5-Fluorouracil-damaged Intestinal Epithelial Cells.

Shizuka Jonan, Mai Haneda, Kikuko Amagase.

   BACKGROUND/AIM: 5-Fluorouracil (5-FU) treatment induces intestinal mucositis, with diarrhea as the primary symptom. Mucositis significantly reduces patients' quality of life (QOL). Amino acids such as glutamate are beneficial for treating gastrointestinal disorders; however, the underlying mechanism remains unclear. Therefore, this study aimed to clarify the role of excitatory amino acid transporters (EAATs) in 5-FU-induced intestinal injury.
MATERIALS AND METHODS: The rat intestinal epithelial cell line (IEC-6) was used to evaluate whether the EAAT inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC) affects 5-FU-induced cytotoxicity. Mice with 5-FU-induced mucositis were used to determine the effects of glutamate on EAATs expression levels.
RESULTS: Treatment with L-trans-PDC suppressed IEC-6 cell growth. It also exacerbated the 5-FU-induced cell growth suppression and increased inflammatory cytokine expression. In addition, mice treated with 5-FU+Glutamate showed higher EAAT1,3 expression than 5-FU only-treated mice.
CONCLUSION: Decreased EAAT levels worsen intestinal cell damage caused by 5-FU, suppress cell growth, and induce inflammation. This study contributes to the understanding EAAT and its relationship with intestinal mucositis, which can aid in the development of novel preventive strategies for cancer chemotherapy.

Keywords:  5-fluorouracil; Excitatory amino acid transporters (EAATs); anti-cancer drug; cytotoxicity; intestinal epithelial cells

DOI:  https://doi.org/10.21873/anticanres.16909
Cell Death Dis. 2024 Feb 28. 15(2): 176

mTOR pathway occupies a central role in the emergence of latent cancer cells.

Kseniia V Aleksandrova, Mikhail L Vorobev, Irina I Suvorova.

The current focus in oncology research is the translational control of cancer cells as a major mechanism of cellular plasticity. Recent evidence has prompted a reevaluation of the role of the mTOR pathway in cancer development leading to new conclusions. The mechanistic mTOR inhibition is well known to be a tool for generating quiescent stem cells and cancer cells. In response to mTOR suppression, quiescent cancer cells dynamically change their proteome, triggering alternative non-canonical translation mechanisms. The shift to selective translation may have clinical relevance, since quiescent tumor cells can acquire new phenotypical features. This review provides new insights into the patterns of mTOR functioning in quiescent cancer cells, enhancing our current understanding of the biology of latent metastasis.

DOI: https://doi.org/10.1038/s41419-024-06547-3
bioRxiv. 2024 Feb 12. pii: 2024.02.11.579776. [Epub ahead of print]

An Organism-Level Quantitative Flux Model of Mammalian Energy Metabolism.

Bo Yuan, Karen E Inouye, Gökhan S Hotamışlıgil, Sheng Hui.

  Mammalian tissues feed on nutrients in the blood circulation. At the organism-level, mammalian energy metabolism comprises of oxidation, interconverting, storing and releasing of circulating nutrients. Though much is known about the individual processes and nutrients, a holistic and quantitative model describing these processes for all major circulating nutrients is lacking. Here, by integrating isotope tracer infusion, mass spectrometry, and isotope gas analyzer measurement, we developed a framework to systematically quantify fluxes through these processes for 10 major circulating energy nutrients in mice, resulting in an organism-level quantitative flux model of energy metabolism. This model revealed in wildtype mice that circulating nutrients' metabolic cycling fluxes are more dominant than their oxidation fluxes, with distinct partition between cycling and oxidation flux for individual circulating nutrients. Applications of this framework in obese mouse models showed on a per animal basis extensive elevation of metabolic cycling fluxes in ob/ob mice, but not in diet-induced obese mice. Thus, our framework describes quantitatively the functioning of energy metabolism at the organism-level, valuable for revealing new features of energy metabolism in physiological and disease conditions.

Keywords:  circulating nutrients; energy metabolism; in vivo flux quantification; isotope tracing; obesity

DOI:  https://doi.org/10.1101/2024.02.11.579776