bims-glucam 2024-11-10 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–11–10
eleven papers selected by
Sreeparna Banerjee, Middle East Technical University

In silico analysis shows slc1a4 as a potential target of hsa-mir-133a for regulating glutamine metabolism in gastric cancer.
Alveolar and Bone Marrow-derived Macrophages Differ in Metabolism and Glutamine Utilization.
Cancer Metabolism: Historical Landmarks, New Concepts, and Opportunities.
Scutellarein inhibits lung cancer growth by inducing cell apoptosis and inhibiting glutamine metabolic pathway.
Exploring the Interplay between the Warburg Effect and Glucolipotoxicity in Cancer Development: A Novel Perspective on Cancer Etiology.
Glutamine modulates neutrophil recruitment and effector functions during sterile inflammation.
The multifaceted modulation of mitochondrial metabolism in tumorigenesis.
Melanoma Metabolism: Molecular Mechanisms and Therapeutic Implications in Cutaneous Oncology.
A Review of Advances in Mitochondrial Research in Cancer.
Dissecting L-glutamine metabolism in acute myeloid leukemia: single-cell insights and therapeutic implications.
Effect of ceftriaxone on the glutamate-glutamine cycle and seizure susceptibility of Tg2576 mouse model of Alzheimer's disease.

Int J Biol Macromol. 2024 Oct 31. pii: S0141-8130(24)07783-3. [Epub ahead of print]282(Pt 5): 136974

In silico analysis shows slc1a4 as a potential target of hsa-mir-133a for regulating glutamine metabolism in gastric cancer.

Averi Chakraborty, Jayasree Patnaik, Anupriya Sinha, Nandita Parida, Tithi Parija, Srinivas Patnaik.

  Cutting-edge research has spotlighted glutamine metabolism as a promising therapeutic target in managing gastric cancer. This investigation highlights the upregulated glutamine transporters by leveraging clinical data from the TCGA Database and the expression analysis of the transcriptome profile of stomach adenocarcinoma (STAD) patients. Notably, it identifies SLC1A4 as a potential glutamine transporter in STAD. The screening of human miRNAs conducted using the TargetScan database, and the subsequent docking analysis present multiple miRNAs with the potential of being explored as therapeutic agents. By integrating transcriptome profiling, miRNA screening, and molecular docking, this study reveals, for the first time, the potential of hsa-mir-133a-1 in targeting slc1a4, along with its known target mTOR, in stomach cancer. The myriad interactions that can be regulated by this silencing mechanism are anticipated to ultimately reduce glutamine uptake in STAD. This study provides compelling evidence of glutamine transport via SLC1A4 in stomach cancer and delves into how it might impact mTOR and some of its pivotal downstream molecules. Considering these findings, novel therapeutic strategies can be devised to further enhance existing methods for combating gastric cancer.

Keywords:  Glutamine; Molecular docking; mTOR, slc1a4, TCGA; miRNA

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.136974
Am J Respir Cell Mol Biol. 2024 Nov 05.

Alveolar and Bone Marrow-derived Macrophages Differ in Metabolism and Glutamine Utilization.

Christine L Vigeland, Jordan D Link, Henry S Beggs, Yazan Alwarawrah, Brandie M Ehrmann, Hong Dang, Claire M Doerschuk.

  Changes in metabolic activity are key regulators of macrophage activity. Pro-inflammatory macrophages upregulate glycolysis, which promotes an inflammatory phenotype, whereas pro-repair macrophages rely upon oxidative metabolism and glutaminolysis to support their activity. Work to understand how metabolism regulates macrophage phenotype has been done primarily in macrophage cell lines and bone marrow-derived macrophages (BMDM). Our study sought to understand changes in metabolic activity of murine tissue-resident alveolar macrophages (AM) in response to LPS stimulation and to contrast them to BMDM. These studies also determined the contribution of glutamine metabolism using the glutamine inhibitor, DON. We found that compared to BMDM, AM have higher rates of oxygen consumption and contain a higher concentration of intracellular metabolites involved in fatty acid oxidation. In response to LPS, BMDM but not AM increased rates of glycolysis. Inhibition of glutamine metabolism using DON altered the metabolic activity of AM but not BMDM. Within AM, glutamine inhibition led to increases in intracellular metabolites involved in glycolysis, the TCA cycle, fatty acid oxidation, and amino acid metabolism. Glutamine inhibition also altered the metabolic response to LPS within AM but not BMDM. Our data reveal striking differences in the metabolic activity of AM and BMDM.

Keywords:  glutamine; glycolysis; lipids; macrophage; metabolomics

DOI:  https://doi.org/10.1165/rcmb.2023-0249OC
Cold Spring Harb Perspect Med. 2024 Nov 05. pii: a041814. [Epub ahead of print]

Cancer Metabolism: Historical Landmarks, New Concepts, and Opportunities.

Navdeep S Chandel, Karen H Vousden, Ralph J DeBerardinis.

Cancer cells undergo changes in metabolism that distinguish them from non-malignant tissue. These may provide a growth advantage by promoting oncogenic signaling and redirecting intermediates to anabolic pathways that provide building blocks for new cellular components. Cancer metabolism is far from uniform, however, and recent work has shed light on its heterogenity within and between tumors. This work is also revealing how cancer metabolism adapts to the tumor microenvironment, as well as ways in which we may capitalize on metabolic changes in cancer cells to create new therapies.

DOI: https://doi.org/10.1101/cshperspect.a041814
J Ethnopharmacol. 2024 Oct 26. pii: S0378-8741(24)01298-4. [Epub ahead of print] 118999

Scutellarein inhibits lung cancer growth by inducing cell apoptosis and inhibiting glutamine metabolic pathway.

Di Zhang, Yinwen Wang, Peng Yu, Jiayi Sun, Jingyang Li, Yingfan Hu, Xianli Meng, Juan Li, Li Xiang.

   ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria baicalensis Georgi, a widely used Chinese medicinal herb, has shown effectiveness against lung cancer. Scutellarein, a key component of Scutellaria baicalensis, also demonstrates anticancer properties in lung cancer. However, the underlying mechanisms have not yet been clarified.
AIM OF THE STUDY: This study aimed to investigate the effects of scutellarein in the treatment of NSCLC and its underlying mechanisms.
METHODS: This study explored the effects of scutellarein on non-small cell lung cancer (NSCLC) and its mechanisms. A Lewis lung cancer mouse model was established to assess scutellarein's anticancer activity in vivo. Additionally, the compound's effects on cell proliferation, colony formation, migration, and apoptosis were evaluated in vitro using A549 and H1299 lung cancer cells. Metabolomics analysis was conducted to identify changes in cellular metabolism due to scutellarein, while molecular docking and western blotting techniques were employed to elucidate the molecular mechanisms of its anti-lung cancer effects.
RESULTS: Scutellarein significantly inhibited lung cancer xenograft tumor growth. In vitro studies showed that scutellarein suppressed migration and colony formation in A549 and H1299 cells, induced cell cycle arrest, and triggered cell apoptosis. Notably, scutellarein profoundly altered amino acid metabolism, particularly affecting glutamine metabolites. It affected key glutamine transporters ASCT2 and LAT1, as well as glutaminase GLS1, leading to their reduced expression.
CONCLUSION: Scutellarein effectively inhibits lung cancer growth both in vivo and in vitro by inducing cell apoptosis and downregulating the glutamine metabolic pathway.

Keywords:  Scutellarein; cell apoptosis; glutamine metabolic pathway; metabolomics; non–small cell lung cancer

DOI:  https://doi.org/10.1016/j.jep.2024.118999
Adv Pharm Bull. 2024 Oct;14(3): 705-713

Exploring the Interplay between the Warburg Effect and Glucolipotoxicity in Cancer Development: A Novel Perspective on Cancer Etiology.

Maher Monir Akl, Amr Ahmed.

  The Warburg effect, first observed by Otto Warburg in the 1920s, delineates a metabolic phenomenon in which cancer cells exhibit heightened glucose uptake and lactate production, even under normoxic conditions. This metabolic shift towards glycolysis, despite the presence of oxygen, fuels the energy demands of rapidly proliferating cancer cells. Dysregulated glucose metabolism, characterized by the overexpression of glucose transporters and the redirection of metabolic pathways towards glycolysis, lies at the crux of this metabolic reprogramming. Consequently, the accumulation of lactate as a byproduct contributes to the creation of an acidic tumor microenvironment, fostering tumor progression and metastasis. However, recent research, notably proposed by Maher Akl, introduces a novel perspective regarding the role of glycolipids in cancer metabolism. Akl's glucolipotoxicity hypothesis posits that aberrant glycolipid metabolism, specifically the intracellular buildup of glycolipids, significantly influences tumor initiation and progression. This hypothesis underscores the disruptive impact of accumulated glycolipids on cellular homeostasis, thereby activating oncogenic pathways and promoting carcinogenesis. This perspective aims to synthesize the intricate mechanisms underlying both the Warburg effect and glucolipotoxicity, elucidating their collective contributions to tumor growth and malignancy. By comprehensively understanding these metabolic aberrations, novel avenues for therapeutic intervention targeting the fundamental drivers of cancer initiation and progression emerge, holding promise for more efficacious treatment strategies in the future.

Keywords:  Cancer etiology; Glycolipid metabolism; Metabolic paradox; Oncogenic pathways; Tumor development

DOI:  https://doi.org/10.34172/apb.2024.049
J Leukoc Biol. 2024 Nov 06. pii: qiae243. [Epub ahead of print]

Glutamine modulates neutrophil recruitment and effector functions during sterile inflammation.

Katharina E M Hellenthal, Katharina Thomas, Nadine Ludwig, Anika Cappenberg, Lena Schemmelmann, Tobias Tekath, Andreas Margraf, Sina Mersmann, Katharina Henke, Jan Rossaint, Alexander Zarbock, Wida Amini.

  During sterile inflammation, tissue damage induces excessive activation and infiltration of neutrophils into tissues, where they critically contribute to organ dysfunction. Tight regulation of neutrophil migration and their effector functions is crucial to prevent overshooting immune responses. Neutrophils utilize more glutamine, the most abundant free α-amino acid in the human blood, than other leukocytes. However, under inflammatory conditions, the body's requirements exceed its ability to produce sufficient amounts of glutamine. This study investigates the impact of glutamine on neutrophil recruitment and their key effector functions. Glutamine treatment effectively reduced neutrophil activation by modulating β2-integrin activity and chemotaxis in vitro. In a murine in vivo model of sterile inflammation induced by renal ischemia-reperfusion injury, glutamine administration significantly attenuated neutrophil recruitment into injured kidneys. Transcriptomic analysis revealed, glutamine induces transcriptomic reprogramming in murine neutrophils, thus improving mitochondrial functionality and glutathione metabolism. Further, glutamine influenced key neutrophil effector functions, leading to decreased production of reactive oxygen species and formation of neutrophil extracellular traps. Mechanistically, we used a transglutaminase 2 inhibitor to identify transglutaminase 2 as a downstream mediator of glutamine effects on neutrophils. In conclusion, our findings suggest that glutamine diminishes activation and recruitment of neutrophils and thus identify glutamine as a potent means to curb overshooting neutrophil responses during sterile inflammation.

Keywords:  NET formation; ROS production; glutamine; neutrophil recruitment

DOI:  https://doi.org/10.1093/jleuko/qiae243
Mitochondrion. 2024 Nov 04. pii: S1567-7249(24)00135-1. [Epub ahead of print] 101977

The multifaceted modulation of mitochondrial metabolism in tumorigenesis.

Rajendiran Keerthiga, Yafang Xie, Desheng Pei, Ailing Fu.

  Changes in mitochondrial metabolism produce a malignant transformation from normal cells to tumor cells. Mitochondrial metabolism, comprising bioenergetic metabolism, biosynthetic process, biomolecular decomposition, and metabolic signal conversion, obviously forms a unique sign in the process of tumorigenesis. Several oncometabolites produced by mitochondrial metabolism maintain tumor phenotype, which are recognized as tumor indicators. The mitochondrial metabolism synchronizes the metabolic and genetic outcome to the potent tumor microenvironmental signals, thereby further promoting tumor initiation. Moreover, the bioenergetic and biosynthetic metabolism within tumor mitochondria orchestrates dynamic contributions toward cancer progression and invasion. In this review, we describe the contribution of mitochondrial metabolism in tumorigenesis through shaping several hallmarks such as microenvironment modulation, plasticity, mitochondrial calcium, mitochondrial dynamics, and epithelial-mesenchymal transition. The review will provide a new insight into the abnormal mitochondrial metabolism in tumorigenesis, which will be conducive to tumor prevention and therapy through targeting tumor mitochondria.

Keywords:  EMT-MET transition; OXPHOS; Oncometabolites; Plasticity; TCA cycle; Tumorigenesis

DOI:  https://doi.org/10.1016/j.mito.2024.101977
Cancer Med. 2024 Nov;13(21): e70386

Melanoma Metabolism: Molecular Mechanisms and Therapeutic Implications in Cutaneous Oncology.

Isabella J Tan, Aarushi K Parikh, Bernard A Cohen.

   BACKGROUND: Melanoma, a highly aggressive skin cancer, is characterized by rapid progression and a high metastatic potential, presenting significant challenges in clinical oncology. A critical aspect of melanoma biology is its metabolic reprogramming, which supports tumor growth, survival, and therapeutic resistance.
OBJECTIVE: This review aims to explore the key molecular mechanisms driving metabolic alterations in melanoma and their implications for developing therapeutic strategies.
METHODS: A Pubmed search was conducted to analyze literature discussing key mechanisms of the Warburg effect, mitochondrial dysfunction, enhanced lipid metabolism, epigenetic modifications, and the tumor microenvironment.
RESULTS: Metabolic reprogramming supports melanoma growth, proliferation, and survival. Understanding these complex metabolic dynamics provides valuable insights for developing targeted therapeutic strategies.
CONCLUSION: Potential therapeutic interventions aimed at disrupting melanoma metabolism highlight the promise of precision medicine in improving treatment outcomes in cutaneous oncology. By targeting metabolic vulnerabilities, novel treatment approaches could significantly enhance the clinical management and prognosis of melanoma.

Keywords:  Warburg effect; epigenetics; melanoma; metabolic reprogramming; metabolism

DOI:  https://doi.org/10.1002/cam4.70386
Cancer Control. 2024 Jan-Dec;31:31 10732748241299072

A Review of Advances in Mitochondrial Research in Cancer.

Zhiru Li, Wu Zhang, Shaowei Guo, Guoyan Qi, Jiandi Huang, Jin Gao, Jing Zhao, Lin Kang, Qingxia Li.

   BACKGROUND: Abnormalities in mitochondrial structure or function are closely related to the development of malignant tumors. Mitochondrial metabolic reprogramming provides precursor substances and energy for the vital activities of tumor cells, so that cancer cells can rapidly adapt to the unfavorable environment of hypoxia and nutrient deficiency. Mitochondria can enable tumor cells to gain the ability to proliferate, escape immune responses, and develop drug resistance by altering constitutive junctions, oxidative phosphorylation, oxidative stress, and mitochondrial subcellular relocalization. This greatly reduces the rate of effective clinical control of tumors.
PURPOSE: Explore the major role of mitochondria in cancer, as well as targeted mitochondrial therapies and mitochondria-associated markers.
CONCLUSIONS: This review provides a comprehensive analysis of the various aspects of mitochondrial aberrations and addresses drugs that target mitochondrial therapy, providing a basis for clinical mitochondria-targeted anti-tumor therapy.

Keywords:  cancer; immune microenvironment; metabolic reprogramming; mitochondria-targeting; mitochondrial dysfunction

DOI:  https://doi.org/10.1177/10732748241299072
J Transl Med. 2024 Nov 06. 22(1): 1002

Dissecting L-glutamine metabolism in acute myeloid leukemia: single-cell insights and therapeutic implications.

Yanli Chen.

   BACKGROUND: Acute myeloid leukemia (AML) is a rapidly progressing blood cancer. The prognosis of AML can be challenging, emphasizing the need for ongoing research and innovative approaches to improve outcomes in individuals affected by this formidable hematologic malignancy.
METHODS: In this study, we used single-cell RNA sequencing (scRNA-seq) from AML patients to investigate the impact of L-glutamine metabolism-related genes on disease progression.
RESULTS: Our analysis revealed increased glutamine-related activity in CD34 + pre-B cells, suggesting a potential regulatory role in tumorigenesis and AML progression. Furthermore, intercellular communication analysis revealed a significant signaling pathway involving macrophage migration inhibitory factor signaling through CD74 + CD44 within CD34 + pre-B cells, which transmit signals to pre-dendritic cells and monocytes. Ligands for this pathway were predominantly expressed in stromal cells, naïve T cells, and CD34 + pre-B cells. CD74, the pertinent receptor, was predominantly detected in a variety of cellular components, including stromal cells, pre-dendritic cells, plasmacytoid dendritic cells, and hematopoietic progenitors. The study's results provide insights into the possible interplay among these cell types and their collective contribution to the pathogenesis of AML. Moreover, we identified 10 genes associated with AML prognosis, including CCL5, CD52, CFD, FABP5, LGALS1, NUCB2, PSAP, S100A4, SPINK2, and VCAN. Among these, CCL5 and CD52 have been implicated in AML progression and are potential therapeutic targets.
CONCLUSIONS: This thorough examination of AML biology significantly deepens our grasp of the disease and presents pivotal information that could guide the creation of innovative treatment strategies for AML patients.

Keywords:  Acute myeloid leukemia; Diagnosis model; L-glutamine metabolism; scRNA-seq

DOI:  https://doi.org/10.1186/s12967-024-05779-3
J Alzheimers Dis. 2024 Nov 03. 13872877241289053

Effect of ceftriaxone on the glutamate-glutamine cycle and seizure susceptibility of Tg2576 mouse model of Alzheimer's disease.

Hattapark Dejakaisaya, Runxuan Lin, Anna Harutyunyan, Jianxiong Chan, Patrick Kwan, Nigel C Jones.

   BACKGROUND: Individuals with Alzheimer's disease (AD) have a heightened risk of epilepsy. However, the underlying mechanisms are not well-understood.
OBJECTIVE: We aimed to elucidate the role of the glutamate-glutamine cycle in this mechanism and test the effect of ceftriaxone, a glutamate transporter-1 (GLT-1) enhancer, on seizure susceptibility in the Tg2576 mouse model of AD.
METHODS: First, we assessed expression levels of key proteins in the glutamate-glutamine cycle in Tg2576 (n = 7) and wild-type littermates (n = 7), and subsequently in the kindling model of epilepsy (n = 6) and sham (n = 6). Then, kindling susceptibility was assessed in three groups: 200 mg/kg ceftriaxone-treated Tg2576 (Tg-Ceft, n = 9); saline-treated Tg2576 (Tg-Sal, n = 9); and saline-treated wild-type (WT-Sal, n = 15). Mice were treated for seven days before kindling, and seizure susceptibility compared between groups.
RESULTS: Protein levels of GLT-1 (p = 0.0093) and glutamine synthetase (p = 0.0016) were reduced in cortex of Tg2576 mice, compared to WT. Kindling increased GLT-1 (cortex: p < 0.0001, hippocampus: p = 0.0075), and glutaminase (cortex: p = 0.0044) protein levels, compared to sham. Both Tg-Ceft and WT-Sal displayed Class IV seizures in response to the first stimulation (p > 0.99), while Tg-Sal displayed Class V seizure (p = 0.0212 versus WT-Sal). Seizure susceptibility of Tg-Ceft was not different from Tg-Sal (p > 0.05), and kindling rates did not differ between groups.
CONCLUSIONS: Disruptions to key components of the glutamate-glutamine cycle are observed in models of AD and epilepsy. However, increasing GLT-1 through ceftriaxone treatment did not influence seizure susceptibility in Tg2576 mice, suggesting this is not an effective strategy to lower seizure susceptibility in AD, or a higher dosage is needed.

Keywords:  Alzheimer's disease; GLT-1; astrocyte; ceftriaxone; dementia; epilepsy model; excitotoxicity; glutamate; glutamate-glutamine cycle; kindling

DOI:  https://doi.org/10.1177/13872877241289053