bims-glucam 2024-02-11 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024‒02‒11
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic Pathways to Promote Tumor Growth.
LncRNA SNHG11 reprograms glutaminolysis in hepatic stellate cells via Wnt/β-catenin/GLS axis.
Stem Cell Theory of Cancer: Clinical Implications for Cellular Metabolism and Anti-Cancer Metabolomics.
Long-term cadmium exposure induces epithelial-mesenchymal transition in breast cancer cells by activating CYP1B1-mediated glutamine metabolic reprogramming in BT474 cells and MMTV-Erbb2 mice.
Glutaminolysis of CD4+ T Cells: A Potential Therapeutic Target in Viral Diseases.
Targeting MYC induces lipid droplet accumulation by upregulation of HILPDA in clear cell renal cell carcinoma.
13C-Metabolic flux analysis detected a hyperoxemia-induced reduction of tricarboxylic acid cycle metabolism in granulocytes during two models of porcine acute subdural hematoma and hemorrhagic shock.
Recent advances in nanomedicine for metabolism-targeted cancer therapy.
Inferring cancer metabolism from gene-expression data.
Tumor-targeted metabolic inhibitor prodrug labelled with cyanine dyes enhances immunoprevention of lung cancer.
Glutamine sustains energy metabolism and alleviates liver injury in burn sepsis by promoting the assembly of mitochondrial HSP60-HSP10 complex via SIRT4 dependent protein deacetylation.
Glutamine transporter SLC38A3 promotes breast cancer metastasis via Gsk3β/β-catenin/EMT pathway.
M2 macrophages secrete glutamate-containing extracellular vesicles to alleviate osteoporosis by reshaping osteoclast precursor fate.
Glutaminolysis inhibition boosts photodynamic therapy to eliminate cancer stem cells.
GPX3-Mediated Oxidative Stress Affects Pyrimidine Metabolism Levels in Stomach Adenocarcinoma via the AMPK/mTOR Pathway.
GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progresses of gastric cancer.
A Multi-Omics Approach Reveals Enrichment in Metabolites Involved in the Regulation of the Glutathione Pathway in LIN28B-Dependent Cancer Cells.

Cancers (Basel). 2024 Jan 24. pii: 504. [Epub ahead of print]16(3):

Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic Pathways to Promote Tumor Growth.

Marilyn Mathew, Nhi T Nguyen, Yangzom D Bhutia, Sathish Sivaprakasam, Vadivel Ganapathy.

  Aerobic glycolysis in cancer cells, originally observed by Warburg 100 years ago, which involves the production of lactate as the end product of glucose breakdown even in the presence of adequate oxygen, is the foundation for the current interest in the cancer-cell-specific reprograming of metabolic pathways. The renewed interest in cancer cell metabolism has now gone well beyond the original Warburg effect related to glycolysis to other metabolic pathways that include amino acid metabolism, one-carbon metabolism, the pentose phosphate pathway, nucleotide synthesis, antioxidant machinery, etc. Since glucose and amino acids constitute the primary nutrients that fuel the altered metabolic pathways in cancer cells, the transporters that mediate the transfer of these nutrients and their metabolites not only across the plasma membrane but also across the mitochondrial and lysosomal membranes have become an integral component of the expansion of the Warburg effect. In this review, we focus on the interplay between these transporters and metabolic pathways that facilitates metabolic reprogramming, which has become a hallmark of cancer cells. The beneficial outcome of this recent understanding of the unique metabolic signature surrounding the Warburg effect is the identification of novel drug targets for the development of a new generation of therapeutics to treat cancer.

Keywords:  aerobic glycolysis; glutamine addiction; glutaminolysis; lactate receptors; nutrient transporters; oncogenes; oncometabolites; one-carbon metabolism; reductive carboxylation; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers16030504
Biochem Pharmacol. 2024 Feb 07. pii: S0006-2952(24)00027-3. [Epub ahead of print] 116044

LncRNA SNHG11 reprograms glutaminolysis in hepatic stellate cells via Wnt/β-catenin/GLS axis.

Kanglei Ying, Yuan Zeng, Jun Xu, Xiao Wu, Huiya Ying, Weimin Cai, Ruoru Zhou, Qian Xu, Xiangting Zhang, Fujun Yu.

  Long non-coding RNAs (lncRNAs) have been identified as decisive regulators of liver fibrosis. Hepatic stellate cells (HSCs), major hepatic cells contributing to liver fibrosis, undergo metabolic reprogramming for transdifferentiation and activation maintenance. As a crucial part of metabolic reprogramming, glutaminolysis fuels the tricyclic acid (TCA) cycle that renders HSCs addicted to glutamine. However, how lncRNAs reprogram glutamine metabolism in HSCs is unknown. For this research, we characterized the pro-fibrogenic function of small nucleolar host gene 11 (SNHG11). Our data showed that in carbon tetrachloride (CCl4, 7 μL/g, intraperitoneally) treated C57BL/6J mice, SNHG11 expression was highly up-regulated in fibrotic livers and activated primary HSCs. SNHG11 knockdown attenuated the accumulation of fibrotic markers α-SMA and Col1A1 in liver fibrosis tissues and activated HSCs. Western blot and qRT-PCR assays demonstrated that glutaminase (GLS), the rate-limiting enzyme for glutaminolysis, was a downstream target of SNHG11. Furthermore, SNHG11 upregulated glutaminolysis in HSCs through the activation of the Wnt/β-catenin signaling pathway. The results highlighted that SNHG11 is a glutaminolysis-regulated lncRNA that promotes liver fibrosis. A novel insight into the metabolic mechanism that reprograms glutaminolysis in HSCs could be exploited as anti-fibrotic targets.

Keywords:  Glutaminase; Hepatic stellate cell; Liver fibrosis; SNHG11; Wnt/β-catenin

DOI:  https://doi.org/10.1016/j.bcp.2024.116044
Cancers (Basel). 2024 Jan 31. pii: 624. [Epub ahead of print]16(3):

Stem Cell Theory of Cancer: Clinical Implications for Cellular Metabolism and Anti-Cancer Metabolomics.

Shi-Ming Tu, Jim Z Chen, Sunny R Singh, Sanjay Maraboyina, Neriman Gokden, Ping-Ching Hsu, Timothy Langford.

  Although Otto Warburg may be right about the role of glycolysis versus OXPHOS in cancer metabolism, it remains unclear whether an altered metabolism is causative or correlative and is the main driver or a mere passenger in the pathogenesis of cancer. Currently, most of our successful treatments are designed to eliminate non-cancer stem cells (non-CSCs) such as differentiated cancer cells. When the treatments also happen to control CSCs or the stem-ness niche, it is often unintended, unexpected, or undetected for lack of a pertinent theory about the origin of cancer that clarifies whether cancer is a metabolic, genetic, or stem cell disease. Perhaps cellular context matters. After all, metabolic activity may be different in different cell types and their respective microenvironments-whether it is in a normal progenitor stem cell vs. progeny differentiated cell and whether it is in a malignant CSC vs. non-CSC. In this perspective, we re-examine different types of cellular metabolism, e.g., glycolytic vs. mitochondrial, of glucose, glutamine, arginine, and fatty acids in CSCs and non-CSCs. We revisit the Warburg effect, an obesity epidemic, the aspartame story, and a ketogenic diet. We propose that a pertinent scientific theory about the origin of cancer and of cancer metabolism influences the direction of cancer research as well as the design of drug versus therapy development in cancer care.

Keywords:  EMT; GLP-1; HIF1-alpha; OXPHOS; PGC-1; aspartame; cancer stem cells; glutamine; glycolysis; ketogenic diet; metabolism; metformin

DOI:  https://doi.org/10.3390/cancers16030624
Sci Total Environ. 2024 Feb 07. pii: S0048-9697(24)00912-4. [Epub ahead of print] 170773

Long-term cadmium exposure induces epithelial-mesenchymal transition in breast cancer cells by activating CYP1B1-mediated glutamine metabolic reprogramming in BT474 cells and MMTV-Erbb2 mice.

Jingdian Li, Peng Gao, Mingke Qin, Junhua Wang, Yan Luo, Ping Deng, Rongrong Hao, Lei Zhang, Mindi He, Chunhai Chen, Yonghui Lu, Qinlong Ma, Min Li, Miduo Tan, Liting Wang, Yang Yue, Hui Wang, Li Tian, Jia Xie, Mengyan Chen, Zhengping Yu, Zhou Zhou, Huifeng Pi.

  Cadmium (Cd) exposure is known to enhance breast cancer (BC) progression. Cd promotes epithelial-mesenchymal transition (EMT) in BC cells, facilitating BC cell aggressiveness and invasion, but the underlying molecular mechanisms are unclear. Hence, transgenic MMTV-Erbb2 mice (6 weeks) were orally administered Cd (3.6 mg/L, approximately equal to 19.64 μΜ) for 23 weeks, and BC cells (BT474 cells) were exposed to Cd (0, 0.1, 1 or 10 μΜ) for 72 h to investigate the effect of Cd exposure on EMT in BC cells. Chronic Cd exposure dramatically expedited tumor metastasis to multiple organs; decreased E-cadherin density; and increased Vimentin, N-cadherin, ZEB1, and Twist density in the tumor tissues of MMTV-Erbb2 mice. Notably, transcriptomic analysis of BC tumors revealed cytochrome P450 1B1 (CYP1B1) as a key factor that regulates EMT progression in Cd-treated MMTV-Erbb2 mice. Moreover, Cd increased CYP1B1 expression in MMTV-Erbb2 mouse BC tumors and in BT474 cells, and CYP1B1 inhibition decreased Cd-induced BC cell malignancy and EMT in BT474 cells. Importantly, the promotion of EMT by CYP1B1 in Cd-treated BC cells was presumably controlled by glutamine metabolism. This study offers novel perspectives into the effect of environmental Cd exposure on driving BC progression and metastasis, and this study provides important guidance for comprehensively assessing the ecological and health risks of Cd.

Keywords:  Breast cancer; CYP1B1; Cadmium; Epithelial–mesenchymal transition; Glutamine metabolism

DOI:  https://doi.org/10.1016/j.scitotenv.2024.170773
J Inflamm Res. 2024 ;17 603-616

Glutaminolysis of CD4+ T Cells: A Potential Therapeutic Target in Viral Diseases.

Yushan Xu, Miaomiao Li, Mengjiao Lin, Dawei Cui, Jue Xie.

  CD4+ T cells play a critical role in the pathogenesis of viral diseases, which are activated by the internal metabolic pathways encountering with viral antigens. Glutaminolysis converts glutamine into tricarboxylic acid (TCA) circulating metabolites by α-ketoglutaric acid, which is essential for the proliferation and differentiation of CD4+ T cells and plays a central role in providing the energy and structural components needed for viral replication after the virus hijacks the host cell. Changes in glutaminolysis in CD4+ T cells are accompanied by changes in the viral status of the host cell due to competition for glutamine between immune cells and host cells. More recently, attempts have been made to treat tumours, autoimmune diseases, and viral diseases by altering the breakdown of glutamine in T cells. In this review, we will discuss the current knowledge of glutaminolysis in the CD4+ T cell subsets from viral diseases, not only increasing our understanding of immunometabolism but also providing a new perspective for therapeutic target in viral diseases.

Keywords:  CD4+ T cells; glutamine; glutaminolysis; immune response; viral diseases

DOI:  https://doi.org/10.2147/JIR.S443482
Proc Natl Acad Sci U S A. 2024 Feb 13. 121(7): e2310479121

Targeting MYC induces lipid droplet accumulation by upregulation of HILPDA in clear cell renal cell carcinoma.

Lourdes Sainero-Alcolado, Elisa Garde-Lapido, Marteinn Thor Snaebjörnsson, Sarah Schoch, Irene Stevens, María Victoria Ruiz-Pérez, Christine Dyrager, Vicent Pelechano, Håkan Axelson, Almut Schulze, Marie Arsenian-Henriksson.

  Metabolic reprogramming is critical during clear cell renal cell carcinoma (ccRCC) tumorigenesis, manifested by accumulation of lipid droplets (LDs), organelles that have emerged as new hallmarks of cancer. Yet, regulation of their biogenesis is still poorly understood. Here, we demonstrate that MYC inhibition in ccRCC cells lacking the von Hippel Lindau (VHL) gene leads to increased triglyceride content potentiating LD formation in a glutamine-dependent manner. Importantly, the concurrent inhibition of MYC signaling and glutamine metabolism prevented LD accumulation and reduced tumor burden in vivo. Furthermore, we identified the hypoxia-inducible lipid droplet-associated protein (HILPDA) as the key driver for induction of MYC-driven LD accumulation and demonstrated that conversely, proliferation, LD formation, and tumor growth are impaired upon its downregulation. Finally, analysis of ccRCC tissue as well as healthy renal control samples postulated HILPDA as a specific ccRCC biomarker. Together, these results provide an attractive approach for development of alternative therapeutic interventions for the treatment of this type of renal cancer.

Keywords:  HILPDA; MYC; clear cell renal cell carcinoma; glutamine; lipid droplets

DOI:  https://doi.org/10.1073/pnas.2310479121
Front Immunol. 2023 ;14 1319986

13C-Metabolic flux analysis detected a hyperoxemia-induced reduction of tricarboxylic acid cycle metabolism in granulocytes during two models of porcine acute subdural hematoma and hemorrhagic shock.

Eva-Maria Wolfschmitt, Josef Albert Vogt, Melanie Hogg, Ulrich Wachter, Nicole Stadler, Thomas Kapapa, Thomas Datzmann, David Alexander Christian Messerer, Andrea Hoffmann, Michael Gröger, Franziska Münz, René Mathieu, Simon Mayer, Tamara Merz, Pierre Asfar, Enrico Calzia, Peter Radermacher, Fabian Zink.

  Introduction: Supplementation with increased inspired oxygen fractions has been suggested to alleviate the harmful effects of tissue hypoxia during hemorrhagic shock (HS) and traumatic brain injury. However, the utility of therapeutic hyperoxia in critical care is disputed to this day as controversial evidence is available regarding its efficacy. Furthermore, in contrast to its hypoxic counterpart, the effect of hyperoxia on the metabolism of circulating immune cells remains ambiguous. Both stimulating and detrimental effects are possible; the former by providing necessary oxygen supply, the latter by generation of excessive amounts of reactive oxygen species (ROS). To uncover the potential impact of increased oxygen fractions on circulating immune cells during intensive care, we have performed a 13C-metabolic flux analysis (MFA) on PBMCs and granulocytes isolated from two long-term, resuscitated models of combined acute subdural hematoma (ASDH) and HS in pigs with and without cardiovascular comorbidity.Methods: Swine underwent resuscitation after 2 h of ASDH and HS up to a maximum of 48 h after HS. Animals received normoxemia (PaO2 = 80 - 120 mmHg) or targeted hyperoxemia (PaO2 = 200 - 250 mmHg for 24 h after treatment initiation, thereafter PaO2 as in the control group). Blood was drawn at time points T1 = after instrumentation, T2 = 24 h post ASDH and HS, and T3 = 48 h post ASDH and HS. PBMCs and granulocytes were isolated from whole blood to perform electron spin resonance spectroscopy, high resolution respirometry and 13C-MFA. For the latter, we utilized a parallel tracer approach with 1,2-13C2 glucose, U-13C glucose, and U-13C glutamine, which covered essential pathways of glucose and glutamine metabolism and supplied redundant data for robust Bayesian estimation. Gas chromatography-mass spectrometry further provided multiple fragments of metabolites which yielded additional labeling information. We obtained precise estimations of the fluxes, their joint credibility intervals, and their relations, and characterized common metabolic patterns with principal component analysis (PCA).
Results: 13C-MFA indicated a hyperoxia-mediated reduction in tricarboxylic acid (TCA) cycle activity in circulating granulocytes which encompassed fluxes of glutamine uptake, TCA cycle, and oxaloacetate/aspartate supply for biosynthetic processes. We further detected elevated superoxide levels in the swine strain characterized by a hypercholesterolemic phenotype. PCA revealed cell type-specific behavioral patterns of metabolic adaptation in response to ASDH and HS that acted irrespective of swine strains or treatment group.
Conclusion: In a model of resuscitated porcine ASDH and HS, we saw that ventilation with increased inspiratory O2 concentrations (PaO2 = 200 - 250 mmHg for 24 h after treatment initiation) did not impact mitochondrial respiration of PBMCs or granulocytes. However, Bayesian 13C-MFA results indicated a reduction in TCA cycle activity in granulocytes compared to cells exposed to normoxemia in the same time period. This change in metabolism did not seem to affect granulocytes' ability to perform phagocytosis or produce superoxide radicals.

Keywords:  Bayesian modeling; glucose metabolism; glutamine utilization; hyperoxia; immunometabolism; mass isotopomer distribution; peripheral blood mononuclear cells; reactive oxygen species

DOI:  https://doi.org/10.3389/fimmu.2023.1319986
Chem Commun (Camb). 2024 Feb 07.

Recent advances in nanomedicine for metabolism-targeted cancer therapy.

Jun Da, XinJia Di, YuQi Xie, JiLi Li, LiLi Zhang, YanLan Liu.

Metabolism denotes the sum of biochemical reactions that maintain cellular function. Different from most normal differentiated cells, cancer cells adopt altered metabolic pathways to support malignant properties. Typically, almost all cancer cells need a large number of proteins, lipids, nucleotides, and energy in the form of ATP to support rapid division. Therefore, targeting tumour metabolism has been suggested as a generic and effective therapy strategy. With the rapid development of nanotechnology, nanomedicine promises to have a revolutionary impact on clinical cancer therapy due to many merits such as targeting, improved bioavailability, controllable drug release, and potentially personalized treatment compared to conventional drugs. This review comprehensively elucidates recent advances of nanomedicine in targeting important metabolites such as glucose, glutamine, lactate, cholesterol, and nucleotide for effective cancer therapy. Furthermore, the challenges and future development in this area are also discussed.

DOI: https://doi.org/10.1039/d3cc05858a
Nat Rev Cancer. 2024 Feb 05.

Inferring cancer metabolism from gene-expression data.

Vakul Mohanty.

DOI: https://doi.org/10.1038/s41568-024-00670-1
Acta Pharm Sin B. 2024 Feb;14(2): 751-764

Tumor-targeted metabolic inhibitor prodrug labelled with cyanine dyes enhances immunoprevention of lung cancer.

Wen Li, Jiali Huang, Chen Shen, Weiye Jiang, Xi Yang, Jingxuan Huang, Yueqing Gu, Zhiyu Li, Yi Ma, Jinlei Bian.

  Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs. To address this challenge, we developed a smart theranostic prodrug system that combines a fluorophore and an anticancer drug, specifically 6-diazo-5-oxo-l-norleucine (DON), using a thioketal linkage (TK). This system enables imaging, chemotherapy, photodynamic therapy, and on-demand drug release upon radiation exposure. The optimized prodrug, DON-TK-BM3, incorporating cyanine dyes as the fluorophore, displayed potent reactive oxygen species release and efficient tumor cell killing. Unlike the parent drug DON, DON-TK-BM3 exhibited no toxicity toward normal cells. Moreover, DON-TK-BM3 demonstrated high tumor accumulation and reduced side effects, including gastrointestinal toxicity, in mice. This study provides a practical strategy for designing prodrugs of metabolic inhibitors with significant toxicity stemming from their lack of tissue selectivity.

Keywords:  Cyanine dye; Glutamine antagonists; Immunotherapy; Metabolic inhibitor; Non-small-cell lung cancer (NSCLC); Photodynamic therapy; Reactive oxygen species; Smart prodrug system

DOI:  https://doi.org/10.1016/j.apsb.2023.10.020
Redox Rep. 2024 Dec;29(1): 2312320

Glutamine sustains energy metabolism and alleviates liver injury in burn sepsis by promoting the assembly of mitochondrial HSP60-HSP10 complex via SIRT4 dependent protein deacetylation.

Yongjun Yang, Qian Chen, Shijun Fan, Yongling Lu, Qianyin Huang, Xin Liu, Xi Peng.

  Burns and burn sepsis, characterized by persistent and profound hypercatabolism, cause energy metabolism dysfunction that worsens organ injury and systemic disorders. Glutamine (Gln) is a key nutrient that remarkably replenishes energy metabolism in burn and sepsis patients, but its exact roles beyond substrate supply is unclear. In this study, we demonstrated that Gln alleviated liver injury by sustaining energy supply and restoring redox balance. Meanwhile, Gln also rescued the dysfunctional mitochondrial electron transport chain (ETC) complexes, improved ATP production, reduced oxidative stress, and protected hepatocytes from burn sepsis injury. Mechanistically, we revealed that Gln could activate SIRT4 by upregulating its protein synthesis and increasing the level of Nicotinamide adenine dinucleotide (NAD+), a co-enzyme that sustains the activity of SIRT4. This, in turn, reduced the acetylation of shock protein (HSP) 60 to facilitate the assembly of the HSP60-HSP10 complex, which maintains the activity of ETC complex II and III and thus sustain ATP generation and reduce reactive oxygen species release. Overall, our study uncovers a previously unknown pharmacological mechanism involving the regulation of HSP60-HSP10 assembly by which Gln recovers mitochondrial complex activity, sustains cellular energy metabolism and exerts a hepato-protective role in burn sepsis.

Keywords:  Glutamine; HSP60-HSP10 assembly; Sirtuin 4; burn sepsis; energy metabolism; liver injury; mitochondrial electron transport chain; reactive oxygen species

DOI:  https://doi.org/10.1080/13510002.2024.2312320
Cancer Lett. 2024 Feb 01. pii: S0304-3835(24)00047-8. [Epub ahead of print] 216653

Glutamine transporter SLC38A3 promotes breast cancer metastasis via Gsk3β/β-catenin/EMT pathway.

Zheqiong Tan, Keerti Boyapati, Caitlin M Tressler, Nicole Jenkinson, Kristine Glunde.

  Breast cancer is the leading cancer-related cause of death in women. Here we show that solute carrier family 38-member 3 (SLC38A3) is overexpressed in breast cancer, particularly in TNBC cells and tissues. Our study reveals that SLC38A3 regulates cellular glutamine, glutamate, asparagine, aspartate, alanine, and glutathione (GSH) levels in breast cancer cells. Our data demonstrate that SLC38A3 enhances cell viability, cell migration and invasion in vitro, and promotes tumor growth and metastasis in vivo, while reducing apoptosis and oxidative stress. Mechanistically, we show that SLC38A3 suppresses the activity of glycogen synthase kinase 3-β (Gsk3β), a negative regulator of β-catenin, and increases protein levels of β-catenin, leading to the upregulation of epithelial-to-mesenchymal-transition (EMT)-inducing transcription factors and EMT markers in breast cancer. In summary, we show that SLC38A3 is overexpressed in breast cancer and promotes breast cancer metastasis via the GSK3β/β-catenin/EMT pathway, presenting a novel therapeutic target to explore for breast cancer.

Keywords:  Antioxidant; Breast cancer; Glutamine; Metabolism; Metastasis; SLC38A3

DOI:  https://doi.org/10.1016/j.canlet.2024.216653
Mol Ther. 2024 Feb 07. pii: S1525-0016(24)00074-1. [Epub ahead of print]

M2 macrophages secrete glutamate-containing extracellular vesicles to alleviate osteoporosis by reshaping osteoclast precursor fate.

Xiaoyuan Huang, Yanhua Lan, Jiahui Shen, Xiaomin Zhao, Yanyan Zhou, Wenzhi Wu, Jiajie Mao, Yuzhu Wu, Zhijian Xie, Zhuo Chen.

  Osteoclast precursors (OCPs) are thought to commit to osteoclast differentiation, which is accelerated by aging-related chronic inflammation, thereby leading to osteoporosis. However, whether the fate of OCPs can be reshaped to transition into other cell lineages is unknown. Here, we showed that M2 macrophage-derived extracellular vesicles (M2-EVs) could reprogram OCPs to downregulate osteoclast-specific gene expression and convert OCPs to M2 macrophage-like lineage cells, which reshaped the fate of OCPs by delivering the molecular metabolite glutamate. Upon delivery of glutamate, glutamine metabolism in OCPs was markedly enhanced, resulting in increased production of α-ketoglutarate (αKG), which participates in Jmjd3-dependent epigenetic reprogramming, causing M2-like macrophage differentiation. Thus, we revealed a novel transformation of OCPs into M2-like macrophages via M2-EVs-initiated metabolic reprogramming and epigenetic modification. Our findings suggest that M2-EVs can reestablish the balance between osteoclasts and M2 macrophages, alleviate the symptoms of bone loss, and constitute a new approach for bone-targeted therapy to treat osteoporosis.

Keywords:  extracellular vesicles; macrophage; metabolic–epigenetic reprogramming; osteoclast; osteoporosis

DOI:  https://doi.org/10.1016/j.ymthe.2024.02.005
Biomaterials. 2024 Feb 02. pii: S0142-9612(24)00031-0. [Epub ahead of print]306 122497

Glutaminolysis inhibition boosts photodynamic therapy to eliminate cancer stem cells.

Qiang Wang, Shiyou Li, Chen Xu, Xing Wang, Tian Yang, Chong Wang, Yuxuan Xiong, Zhijie Zhang, Xiangliang Yang, Zifu Li.

  High reactive oxygen species (ROS) levels provide a therapeutic opportunity to eradicate cancer stem cells (CSCs), a population of cells responsible for tumorigenesis, progression, metastasis, and recurrence. However, enhanced antioxidant systems in this population of cells attenuate ROS-inducing therapies. Here, we developed a nanoparticle-assisted combination therapy to eliminate CSCs by employing photodynamic therapy (PDT) to yield ROS while disrupting ROS defense with glutaminolysis inhibition. Specifically, we leveraged an oleic acid-hemicyanine conjugate (CyOA) as photosensitizer, a new entity molecule HYL001 as glutaminolysis inhibitor, and a biocompatible folic acid-hydroxyethyl starch conjugate (FA-HES) as amphiphilic surfactant to construct cellular and mitochondrial hierarchical targeting nanomedicine (COHF NPs). COHF NPs inhibited glutaminolysis to reduce intracellular ROS scavengers, including glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH), and to blunt oxidative phosphorylation (OXPHOS) for oxygen-conserved PDT. Compared to COLF NPs without glutaminolysis inhibitor, COHF NPs exhibited higher phototoxicity to breast cancer stem cells (BCSCs) both in vitro and in vivo. More importantly, we corroborated that marketed glutaminolysis inhibitors, such as CB839 and V9302, augment the clinically used photosensitizer (Hiporfin) for BCSCs elimination. This study develops a potent CSCs targeting strategy by combining glutaminolysis inhibition with PDT and provides significant implications for cancer therapy.

Keywords:  Cancer stem cells; Glutaminolysis inhibition; Nanomedicine; Oxidative stress; Photodynamic therapy

DOI:  https://doi.org/10.1016/j.biomaterials.2024.122497
Int J Clin Pract. 2024 ;2024 6875417

GPX3-Mediated Oxidative Stress Affects Pyrimidine Metabolism Levels in Stomach Adenocarcinoma via the AMPK/mTOR Pathway.

Yaowen Zhang, Yixin Yang, Shanshan Kuang, Yang Zhang, Hancheng Qin, Jisheng Xie.

Background: Amino acid metabolism, including ATP production, nucleotide synthesis, and redox homeostatic processes, are associated with proliferation and differentiation of tumor cells. This study aimed to identify novel prognostic biomarkers and potential therapeutic targets of amino acid metabolism-related genes for stomach adenocarcinoma (STAD).Methods: RNA sequencing transcriptome data in the TCGA-STAD (training set) and GTEx datasets (validation set) were used. The LIMMA R program enabled the differentially expressed amino acid metabolism-related genes (AAMRGs) to be found. A prognostic risk score model based on clinical phenotypic features was built using LASSO regression and step multi-Cox analyses. Gene set enrichment analysis (GSEA) was used to find potential molecular pathways associated with STAD. Hierarchical cluster analysis was used to evaluate pyrimidine metabolism. Cultured STAD cells assessed the proliferation of STAD and upregulation of GPX3 expression by CCK8 and flow cytometry. Transwell and wound healing assays assessed the impact of GPX3 on invasion and migration of STAD cells. Western blot and qRT-PCR were used to measure changes in pyrimidine metabolism-related markers and active molecules involved in the AMPK/mTOR signaling pathway.
Results: Three AAMRGs, DNMT1, F2R, and GPX3, could independently predict the course of STAD. Pyrimidine metabolism appeared to be significantly associated with these by GSEA and clustering analyses. Pyrimidine metabolism was negatively correlated with GPX3. Functional studies using an overexpressed GPX3 plasmid showed an enhanced migration and invasion of STAD cells as well as the expression of genes associated with pyrimidine metabolism and the AMPK/mTOR signaling pathway. By using a CAD siRNA, it was found that that GPX3 affected 5-fluorouracil resistance during de novo synthesis of pyrimidine through the CAD-UMPS signaling axis.
Conclusions: GPX3 which regulates the level of pyrimidine metabolism through the AMPK/mTOR pathway was found to be closely associated with STAD. Our findings demonstrate GPX3 is a reliable biomarker for the prognosis of amino acid metabolism and a probable target for STAD therapy.

DOI: https://doi.org/10.1155/2024/6875417
Acta Pharm Sin B. 2024 Feb;14(2): 698-711

GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progresses of gastric cancer.

Qiwei Jiang, Yong Li, Songwang Cai, Xingyuan Shi, Yang Yang, Zihao Xing, Zhenjie He, Shengte Wang, Yubin Su, Meiwan Chen, Zhesheng Chen, Zhi Shi.

  Glutamate-ammonia ligase (GLUL, also known as glutamine synthetase) is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation. Although GLUL plays a critical role in multiple cancers, the expression and function of GLUL in gastric cancer remain unclear. In the present study, we have found that the expression level of GLUL was significantly lower in gastric cancer tissues compared with adjacent normal tissues, and correlated with N stage and TNM stage, and low GLUL expression predicted poor survival for gastric cancer patients. Knockdown of GLUL promoted the growth, migration, invasion and metastasis of gastric cancer cells in vitro and in vivo, and vice versa, which was independent of its enzyme activity. Mechanistically, GLUL competed with β-Catenin to bind to N-Cadherin, increased the stability of N-Cadherin and decreased the stability of β-Catenin by alerting their ubiquitination. Furthermore, there were lower N-Cadherin and higher β-Catenin expression levels in gastric cancer tissues compared with adjacent normal tissues. GLUL protein expression was correlated with that of N-Cadherin, and could be the independent prognostic factor in gastric cancer. Our findings reveal that GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progress of gastric cancer.

Keywords:  Enzyme; GLUL; Gastric cancer; N-Cadherin; Protein stability; Protein-protein interaction; Ubiquitination; β-Catenin

DOI:  https://doi.org/10.1016/j.apsb.2023.11.008
Int J Mol Sci. 2024 Jan 27. pii: 1602. [Epub ahead of print]25(3):

A Multi-Omics Approach Reveals Enrichment in Metabolites Involved in the Regulation of the Glutathione Pathway in LIN28B-Dependent Cancer Cells.

Matteo Stocchero, Diana Corallo, Silvia Bresolin, Marcella Pantile, Paola Pirillo, Roberta Bortolozzi, Sara Menegazzo, Daniele Boso, Giampietro Viola, Eugenio Baraldi, Alessandra Biffi, Giuseppe Giordano, Sanja Aveic.

  The RNA-binding protein LIN28B, identified as an independent risk factor in high-risk neuroblastoma patients, is implicated in adverse treatment outcomes linked to metastasis and chemoresistance. Despite its clinical significance, the impact of LIN28B on neuroblastoma cell metabolism remains unexplored. This study employs a multi-omics approach, integrating transcriptome and metabolome data, to elucidate the global metabolic program associated with varying LIN28B expression levels over time. Our findings reveal that escalating LIN28B expression induces a significant metabolic rewiring in neuroblastoma cells. Specifically, LIN28B prompts a time-dependent increase in the release rate of metabolites related to the glutathione and aminoacyl-tRNA biosynthetic pathways, concomitant with a reduction in glucose uptake. These results underscore the pivotal role of LIN28B in governing neuroblastoma cell metabolism and suggest a potential disruption in the redox balance of LIN28B-bearing cells. This study offers valuable insights into the molecular mechanisms underlying LIN28B-associated adverse outcomes in neuroblastoma, paving the way for targeted therapeutic interventions.

Keywords:  LIN28B; glutathione metabolism; metabolome; neuroblastoma; omics integration; transcriptome

DOI:  https://doi.org/10.3390/ijms25031602