bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2022‒10‒16
twenty-two papers selected by
Sreeparna Banerjee
Middle East Technical University
  1. Glutaminolysis and CD4+ T-cell metabolism in autoimmunity: From pathogenesis to therapy prospects.
  2. PGC-1β and ERRα Promote Glutamine Metabolism and Colorectal Cancer Survival via Transcriptional Upregulation of PCK2.
  3. Glutaminase 1 blockade alleviates nonalcoholic steatohepatitis via promoting proline metabolism.
  4. Tumor-targeted dual-starvation therapy based on redox-responsive micelle nanosystem with co-loaded LND and BPTES.
  5. The "Sweet Spot" of Targeting Tumor Metabolism in Ovarian Cancers.
  6. Metabolic Pathways in Breast Cancer Reprograming: An Insight to Non-Coding RNAs.
  7. Cancer-associated fibroblast-specific lncRNA LINC01614 enhances glutamine uptake in lung adenocarcinoma.
  8. Effect of TP53 deficiency and KRAS signaling on the bioenergetics of colon cancer cells in response to different substrates: A single cell study.
  9. Hepatocellular carcinoma stage: an almost loss of fatty acid metabolism and gain of glucose metabolic pathways dysregulation.
  10. CircMAT2B facilitates the progression of head and neck squamous cell carcinoma via sponging miR-491-5p to trigger ASCT2-mediated glutaminolysis.
  11. Sirtuin 4 activates autophagy and inhibits tumorigenesis by upregulating the p53 signaling pathway.
  12. Metabolic Reprogramming in Tumor Endothelial Cells.
  13. Metabolite-derived protein modifications modulating oncogenic signaling.
  14. Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4+ T cell differentiation.
  15. NRF2: A crucial regulator for mitochondrial metabolic shift and prostate cancer progression.
  16. Therapeutic targeting of glutamate dehydrogenase 1 that links metabolic reprogramming and Snail-mediated epithelial-mesenchymal transition in drug-resistant lung cancer.
  17. Reprogramming T-Cell Metabolism for Better Anti-Tumor Immunity.
  18. Therapeutic Drug-Induced Metabolic Reprogramming in Glioblastoma.
  19. The metabolic plasticity of B cells.
  20. Ginsenosides in cancer: A focus on the regulation of cell metabolism.
  21. Src: coordinating metabolism in cancer.
  22. Metabolic communication in the tumour-immune microenvironment.
  1. Front Immunol. 2022 ;13 986847
    Glutaminolysis and CD4+ T-cell metabolism in autoimmunity: From pathogenesis to therapy prospects.
    Xiaojin Feng, Xue Li, Na Liu, Ningning Hou, Xiaodong Sun, Yongping Liu.
      The recent increase in the pathogenesis of autoimmune diseases revealed the critical role of T cells. Investigation into immunometabolism has drawn attention to metabolic processes other than glycometabolism. In rapidly dividing immune cells, including T lymphocytes, the consumption of glutamine is similar to or higher than that of glucose even though glucose is abundant. In addition to contributing to many processes critical for cellular integrity and function, glutamine, as the most abundant amino acid, was recently regarded as an immunomodulatory nutrient. A better understanding of the biological regulation of glutaminolysis in T cells will provide a new perspective for the treatment of autoimmune diseases. In this review, we summarized the current knowledge of glutamine catabolism in CD4+ T-cell subsets of autoimmunity. We also focused on potential treatments targeting glutaminolysis in patients with autoimmune diseases. Knowledge of immunometabolism is constantly evolving, and glutamine metabolism may be a potential therapeutic target for autoimmune disease therapy.
    Keywords:  CD4+ T cells; autoimmune diseases; glutamine; glutaminolysis; immune response
    DOI:  https://doi.org/10.3389/fimmu.2022.986847
  2. Cancers (Basel). 2022 Oct 05. pii: 4879. [Epub ahead of print]14(19):
    PGC-1β and ERRα Promote Glutamine Metabolism and Colorectal Cancer Survival via Transcriptional Upregulation of PCK2.
    Danielle E Frodyma, Thomas C Troia, Chaitra Rao, Robert A Svoboda, Jordan A Berg, Dhananjay D Shinde, Vinai C Thomas, Robert E Lewis, Kurt W Fisher.
      BACKGROUND: Previous studies have shown that Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Beta (PGC-1β) and Estrogen-Related Receptor Alpha (ERRα) are over-expressed in colorectal cancer and promote tumor survival.METHODS: In this study, we use immunoprecipitation of epitope tagged endogenous PGC-1β and inducible PGC-1β mutants to show that amino acid motif LRELL on PGC-1β is responsible for the physical interaction with ERRα and promotes ERRα mRNA and protein expression. We use RNAsequencing to determine the genes regulated by both PGC-1β & ERRα and find that mitochondrial Phosphoenolpyruvate Carboxykinase 2 (PCK2) is the gene that decreased most significantly after depletion of both genes.
    RESULTS: Depletion of PCK2 in colorectal cancer cells was sufficient to reduce anchorage-independent growth and inhibit glutamine utilization by the TCA cycle. Lastly, shRNA-mediated depletion of ERRα decreased anchorage-independent growth and glutamine metabolism, which could not be rescued by plasmid derived expression of PCK2.
    DISCUSSION: These findings suggest that transcriptional control of PCK2 is one mechanism used by PGC-1β and ERRα to promote glutamine metabolism and colorectal cancer cell survival.
    Keywords:  ERRα; K-Ras; PCK2; PGC-1β; colorectal cancer; metabolism; precision medicine
    DOI:  https://doi.org/10.3390/cancers14194879
  3. Biochem Biophys Res Commun. 2022 Oct 04. pii: S0006-291X(22)01392-4. [Epub ahead of print]634 1-9
    Glutaminase 1 blockade alleviates nonalcoholic steatohepatitis via promoting proline metabolism.
    Honghu Tu, Xueyi Yin, Jingjing Wen, Wenbiao Wu, Bo Zhai, Jinlong Li, Haowen Jiang.
      Nonalcoholic steatohepatitis (NASH) is emerging as a major cause of end-stage liver disease, but nowadays no pharmacological therapies are approved and there is an urgent need to develop new therapeutic targets. Glutaminase 1 (GLS1) knockdown had been put forward to alleviate NASH, but its mechanism is still unclear. Herein, to explore the exact relationship between glutamine metabolism and NASH development, we establish a NASH mice model and identified JHU-083, a proven GLS1 inhibitor, could efficiently alleviate NASH. Remarkably, JHU-083 could decrease lipid contents in the liver by enhancing fatty acid oxidation capacity considerably and transcriptomic analysis revealed JHU-083 administration could influence proline metabolism. Then we found the efficacy of JHU-083 on lipid metabolism relied on proline and when proline metabolism was blocked, GLS1 inhibitors no longer worked. Our data suggest that inhibiting glutamine hydrolysis could promote fatty acid oxidation by regulating proline metabolism, which is closely associated with NASH development and could be considered a new possible therapeutic target for NASH therapy.
    Keywords:  Fatty acid oxidation; GLS1 inhibitor; Lipid accumulation; Nonalcoholic steatohepatitis; Proline metabolism
    DOI:  https://doi.org/10.1016/j.bbrc.2022.10.007
  4. Mater Today Bio. 2022 Dec;16 100449
    Tumor-targeted dual-starvation therapy based on redox-responsive micelle nanosystem with co-loaded LND and BPTES.
    Zhenxiang Fu, Huiping Du, Siyu Meng, Mengjiao Yao, Pan Zhao, Xiang Li, Xinmin Zheng, Zhang Yuan, Hui Yang, Kaiyong Cai, Liangliang Dai.
      The starvation therapy mediated by the lonidamine (LND) was limited by the low drug delivery efficiency, off-target effect and compensative glutamine metabolism. Herein, a hyaluronic acid (HA)-modified reduction-responsive micellar nanosystem co-loaded with glycolysis and glutamine metabolism inhibitor (LND and bis-2-(5-phenylacetmido-1,2,4-thiadiazol-2-yl)ethyl sulfide, BPTES) was constructed for tumor-targeted dual-starvation therapy. The in vitro and in vivo results collectively suggested that the fabricated nanosystem could effectively endocytosed by tumor cells via HA receptor-ligand recognition, and rapidly release starvation-inducers LND and BPTES in response to the GSH-rich intratumoral cytoplasm. Furthermore, the released LND and BPTES were capable of inducing glycolysis and glutamine metabolism suppression, and accompanied by significant mitochondrial damage, cell cycle arrest and tumor cells apoptosis, eventually devoting to the blockade of the energy and substance supply and tumor killing with high efficiency. In summary, HPPPH@L@B nanosystem significantly inhibited the compensatory glycolysis and glutamine metabolism via the dual-starvation therapy strategy, blocked the indispensable energy and substance supply of tumors, consequently leading to the desired tumor starvation and effective tumor killing with reliable biosafety.
    Keywords:  Degradable micelle; Drug delivery nanosystem; Dual-starvation therapy; Metabolism suppression; Redox-responsive
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100449
  5. Cancers (Basel). 2022 Sep 27. pii: 4696. [Epub ahead of print]14(19):
    The "Sweet Spot" of Targeting Tumor Metabolism in Ovarian Cancers.
    Katelyn Tondo-Steele, Karen McLean.
      The objective of this review is to explore the metabolomic environment of epithelial ovarian cancer that contributes to chemoresistance and to use this knowledge to identify possible targets for therapeutic intervention. The Warburg effect describes increased glucose uptake and lactate production in cancer cells. In ovarian cancer, we require a better understanding of how cancer cells reprogram their glycogen metabolism to overcome their nutrient deficient environment and become chemoresistant. Glucose metabolism in ovarian cancer cells has been proposed to be influenced by altered fatty acid metabolism, oxidative phosphorylation, and acidification of the tumor microenvironment. We investigate several markers of altered metabolism in ovarian cancer including hypoxia-induced factor 1, VEGF, leptin, insulin-like growth factors, and glucose transporters. We also discuss the signaling pathways involved with these biomarkers including PI3K/AKT/mTOR, JAK/STAT and OXPHOS. This review outlines potential metabolic targets to overcome chemoresistance in ovarian cancer. Continued research of the metabolic changes in ovarian cancer is needed to identify and target these alterations to improve treatment approaches.
    Keywords:  PI3K/AKT/mTOR; fatty acid oxidation; glucose; glycolysis; insulin; leptin; metabolism; metabolomics; ovarian cancer; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/cancers14194696
  6. Cells. 2022 Sep 23. pii: 2973. [Epub ahead of print]11(19):
    Metabolic Pathways in Breast Cancer Reprograming: An Insight to Non-Coding RNAs.
    Fereydoon Abedi-Gaballu, Elham Kamal Kazemi, Seyed Ahmad Salehzadeh, Behnaz Mansoori, Farhad Eslami, Ali Emami, Gholamreza Dehghan, Behzad Baradaran, Behzad Mansoori, William C Cho.
      Cancer cells reprogram their metabolisms to achieve high energetic requirements and produce precursors that facilitate uncontrolled cell proliferation. Metabolic reprograming involves not only the dysregulation in glucose-metabolizing regulatory enzymes, but also the enzymes engaging in the lipid and amino acid metabolisms. Nevertheless, the underlying regulatory mechanisms of reprograming are not fully understood. Non-coding RNAs (ncRNAs) as functional RNA molecules cannot translate into proteins, but they do play a regulatory role in gene expression. Moreover, ncRNAs have been demonstrated to be implicated in the metabolic modulations in breast cancer (BC) by regulating the metabolic-related enzymes. Here, we will focus on the regulatory involvement of ncRNAs (microRNA, circular RNA and long ncRNA) in BC metabolism, including glucose, lipid and glutamine metabolism. Investigation of this aspect may not only alter the approaches of BC diagnosis and prognosis, but may also open a new avenue in using ncRNA-based therapeutics for BC treatment by targeting different metabolic pathways.
    Keywords:  breast cancer; metabolic pathways; non-coding RNA; reprograming
    DOI:  https://doi.org/10.3390/cells11192973
  7. J Hematol Oncol. 2022 Oct 08. 15(1): 141
    Cancer-associated fibroblast-specific lncRNA LINC01614 enhances glutamine uptake in lung adenocarcinoma.
    Tongyan Liu, Chencheng Han, Panqi Fang, Zhifei Ma, Xiaoxiao Wang, Hao Chen, Siwei Wang, Fanchen Meng, Cheng Wang, Erbao Zhang, Guozhang Dong, Hongyu Zhu, Wenda Yin, Jie Wang, Xianglin Zuo, Mantang Qiu, Jinke Wang, Xu Qian, Hongbing Shen, Lin Xu, Zhibin Hu, Rong Yin.
      BACKGROUND: Besides featured glucose consumption, recent studies reveal that cancer cells might prefer "addicting" specific energy substrates from the tumor microenvironment (TME); however, the underlying mechanisms remain unclear.METHODS: Fibroblast-specific long noncoding RNAs were screened using RNA-seq data of our NJLCC cohort, TCGA, and CCLE datasets. The expression and package of LINC01614 into exosomes were identified using flow cytometric sorting, fluorescence in situ hybridization (FISH), and quantitative reverse transcription polymerase chain reaction (RT-PCR). The transfer and functional role of LINC01614 in lung adenocarcinoma (LUAD) and CAFs were investigated using 4-thiouracil-labeled RNA transfer and gain- and loss-of-function approaches. RNA pull-down, RNA immunoprecipitation, dual-luciferase assay, gene expression microarray, and bioinformatics analysis were performed to investigate the underlying mechanisms involved.
    RESULTS: We demonstrate that cancer-associated fibroblasts (CAFs) in LUAD primarily enhance the glutamine metabolism of cancer cells. A CAF-specific long noncoding RNA, LINC01614, packaged by CAF-derived exosomes, mediates the enhancement of glutamine uptake in LUAD cells. Mechanistically, LINC01614 directly interacts with ANXA2 and p65 to facilitate the activation of NF-κB, which leads to the upregulation of the glutamine transporters SLC38A2 and SLC7A5 and eventually enhances the glutamine influx of cancer cells. Reciprocally, tumor-derived proinflammatory cytokines upregulate LINC01614 in CAFs, constituting a feedforward loop between CAFs and cancer cells. Blocking exosome-transmitted LINC01614 inhibits glutamine addiction and LUAD growth in vivo. Clinically, LINC01614 expression in CAFs is associated with the glutamine influx and poor prognosis of patients with LUAD.
    CONCLUSION: Our study highlights the therapeutic potential of targeting a CAF-specific lncRNA to inhibit glutamine utilization and cancer progression in LUAD.
    Keywords:  Cancer-associated fibroblasts; Glutamine; Long noncoding RNA; Metabolic reprograming; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13045-022-01359-4
  8. Front Cell Dev Biol. 2022 ;10 893677
    Effect of TP53 deficiency and KRAS signaling on the bioenergetics of colon cancer cells in response to different substrates: A single cell study.
    James Kealey, Heiko Düssmann, Irene Llorente-Folch, Natalia Niewidok, Manuela Salvucci, Jochen H M Prehn, Beatrice D'Orsi.
      Metabolic reprogramming is a hallmark of cancer. Somatic mutations in genes involved in oncogenic signaling pathways, including KRAS and TP53, rewire the metabolic machinery in cancer cells. We here set out to determine, at the single cell level, metabolic signatures in human colon cancer cells engineered to express combinations of activating KRAS gene mutations and TP53 gene deletions. Specifically, we explored how somatic mutations in these genes and substrate availability (lactate, glucose, substrate deprivation) from the extracellular microenvironment affect bioenergetic parameters, including cellular ATP, NADH and mitochondrial membrane potential dynamics. Employing cytosolic and mitochondrial FRET-based ATP probes, fluorescent NADH sensors, and the membrane-permeant cationic fluorescent probe TMRM in HCT-116 cells as a model system, we observed that TP53 deletion and KRAS mutations drive a shift in metabolic signatures enabling lactate to become an efficient metabolite to replenish both ATP and NADH following nutrient deprivation. Intriguingly, cytosolic, mitochondrial and overall cellular ATP measurements revealed that, in WT KRAS cells, TP53 deficiency leads to an enhanced ATP production in the presence of extracellular lactate and glucose, and to the greatest increase in ATP following a starvation period. On the other hand, oncogenic KRAS in TP53-deficient cells reversed the alterations in cellular ATP levels. Moreover, cell population measurements of mitochondrial and glycolytic metabolism using a Seahorse analyzer demonstrated that WT KRAS TP53-silenced cells display an increase of the basal respiration and tightly-coupled mitochondria, in the presence of glucose as substrate, compared to TP53 competent cells. Furthermore, cells possessing oncogenic KRAS, independently of TP53 status, showed less pronounced mitochondrial membrane potential changes in response to metabolic nutrients. Furthermore, analysis of cytosolic and mitochondrial NADH levels revealed that the simultaneous presence of TP53 deletion and oncogenic KRAS showed the most pronounced alteration in cytosolic and mitochondrial NADH during metabolic stress. In conclusion, our findings demonstrate how activating KRAS mutation and loss of TP53 remodel cancer metabolism and lead to alterations in bioenergetics under metabolic stress conditions by modulating cellular ATP production, NADH oxidation, mitochondrial respiration and function.
    Keywords:  Cancer Metabolism; OxPhos; bioenergetics; colorectal cancer; metabolic stress
    DOI:  https://doi.org/10.3389/fcell.2022.893677
  9. Med Oncol. 2022 Oct 08. 39(12): 247
    Hepatocellular carcinoma stage: an almost loss of fatty acid metabolism and gain of glucose metabolic pathways dysregulation.
    Karthik Balakrishnan.
      Cancer cells rewire the metabolic processes beneficial for cancer cell proliferation, survival, and their progression. In this study, metabolic processes related to glucose, glutamine, and fatty acid metabolism signatures were collected from the molecular signatures database and investigated in the context of energy metabolic pathways through available genome-wide expression profiles of liver cancer cohorts by gene sets-based pathway activation scoring analysis. The outcomes of this study portray that the fatty acid metabolism, transport, and its storage related signatures are highly expressed across early stages of liver tumors and on the contrary, the gene sets related to glucose transport and glucose metabolism are prominently activated in the hepatocellular carcinoma (HCC) stage. Based on the results, these metabolic pathways are clearly dysregulated across specific stages of carcinogenesis. The identified dimorphic metabolic pathway dysregulation patterns are further reconfirmed by examining corresponding metabolic pathway genes expression patterns across various stages encompassing profiles. Recurrence is the primary concern in the carcinogenesis of liver tumors due to liver tissues regeneration. Hence, to further explore these dysregulation effects on recurrent cirrhosis and recurrent HCC sample containing profile GSE20140 was examined and interestingly, this result also reiterated these differential metabolic pathways dysregulation. In addition, a recently established metabolome profile for the massive panel of cancer cell-lines, including liver cancer cell-lines, was used for further exploration. These findings also reassured those differential metabolites abundance of the fatty acid and glucose metabolic pathways enlighten those dimorphic metabolic pathways dysregulation. Moreover, ROC curves of fatty acid metabolic pathway genes such as acetyl-CoA carboxylase (ACACB), acyl-CoA dehydrogenase long chain (ACADL), and acyl-CoA dehydrogenase medium chain (ACADM) as well as glucose metabolic pathway genes such as phosphoglycerate kinase (PGK1), pyruvate dehydrogenase (PDHA1), pyruvate dehydrogenase kinase (PDK1) demonstrated greater sensitivity and specificity in the corresponding stage-specific tumors with significant p-values (p < 0.05). Furthermore, overall survival (OS) and recurrence-free survival (RFS) studies also reconfirmed that the rate-limiting genes expression of fatty acid and glucose metabolic pathways reveal better and poor survival in HCC patient cohorts, respectively. In conclusion, all these results clearly show that metabolic rewiring and the existence of two diverse metabolic pathways dysregulation involving fatty acid and glucose metabolism across the stages of liver tumors have been identified. These findings might be useful for developing therapeutic target treatments in stage-specific tumors.
    Keywords:  Fatty acid metabolism; Glucose metabolism; Hepatocellular carcinoma; Liver cancer
    DOI:  https://doi.org/10.1007/s12032-022-01839-0
  10. Mol Cell Biochem. 2022 Oct 11.
    CircMAT2B facilitates the progression of head and neck squamous cell carcinoma via sponging miR-491-5p to trigger ASCT2-mediated glutaminolysis.
    Jing-Tao Luo, Ya-Fei Wang, Yun Wang, Chun-Li Wang, Ruo-Yan Liu, Ze Zhang.
      Circular RNAs (circRNAs) are well-known to exert significant roles in regulating the pathological processes, including human carcinogenesis. Currently, less is known about their exact roles in head and neck squamous cell carcinoma (HNSCC). Herein, we aimed to investigate and validate the role of a novel circRNA, circMAT2B, as well as its potential molecular mechanism in HNSCC progression. A cohort of 41 paired of HNSCC tumor tissues and adjacent normal tissues from HNSCC patients were collected. Further, we characterized circMAT2B expression patterns in HNSCC tissues and cell lines, as well as exploring its association with the prognosis of HNSCC patients. Biological functions on cell proliferation, apoptosis, migration, and invasion were assessed using Cell Counting Kit-8, EdU incorporation, TUNEL, wound healing, and transwell assays. Glutaminolysis was evaluated by measuring glutamine, glutamate, and α-ketoglutarate (α-KG) levels. The regulatory network of circMAT2B/miR-491-5p/ASCT2 axis was verified by RNA immunoprecipitation and luciferase reporter assays. Western blot was conducted to detect the level of ASCT2 and GLS1. Remarkably overexpressed circMAT2B was observed in HNSCC tissues and cell lines, of which high abundance was positively correlated with patients' poor prognosis. Silencing of circMAT2B inhibited cell proliferation, migration, and invasion, as well as glutaminolysis. miR-491-5p, interacted with ASCT2, was identified to be a downstream target of circMAT2B, thereby involving in circMAT2B-mediated biological effects. In summary, we draw a conclusion that circMAT2B could modulate the processes of cell proliferation, migration, invasion, and glutaminolysis of HNSCC cells partly via the miR-491-5p/ASCT2 axis by a molecular mechanism of competing endogenous RNA (ceRNA), implying an underlying circRNA-targeted therapy for HNSCC treatment.
    Keywords:  ASCT2; CircMAT2B; Glutaminolysis; HNSCC; miR-491-5p
    DOI:  https://doi.org/10.1007/s11010-022-04565-3
  11. Cell Death Differ. 2022 Oct 08.
    Sirtuin 4 activates autophagy and inhibits tumorigenesis by upregulating the p53 signaling pathway.
    Juan Li, Hanxiang Zhan, Yidan Ren, Maoxiao Feng, Qin Wang, Qinlian Jiao, Yuli Wang, Xiaoyan Liu, Shujun Zhang, Lutao Du, Yunshan Wang, Chuanxin Wang.
      The role of autophagy in cancer is context-dependent. In the present study, we aimed to investigate the regulator and underlying mechanism of autophagy. We found that a sirtuin (SIRT) family member, SIRT4, was significantly associated autophagy pathway in pancreatic ductal adenocarcinoma (PDAC). Specifically, in vitro cell culture experiments and in vivo transgenic and xenografted animal models revealed that SIRT4 could inhibit tumor growth and promote autophagy in PDAC. In terms of the mechanism, we demonstrated that SIRT4 activated the phosphorylation of p53 protein by suppressing glutamine metabolism, which was crucial in SIRT4-induced autophagy. AMPKα was implicated in the regulation of autophagy and phosphorylation of p53 mediated by SIRT4, contributing to the suppression of pancreatic tumorigenesis. Notably, the clinical significance of the SIRT4/AMPKα/p53/autophagy axis was demonstrated in human PDAC specimens. Collectively, these findings suggested that SIRT4-induced autophagy further inhibited tumorigenesis and progression of PDAC, highlighting the potential of SIRT4 as a therapeutic target for cancer.
    DOI:  https://doi.org/10.1038/s41418-022-01063-3
  12. Int J Mol Sci. 2022 Sep 21. pii: 11052. [Epub ahead of print]23(19):
    Metabolic Reprogramming in Tumor Endothelial Cells.
    Melissa García-Caballero, Liliana Sokol, Anne Cuypers, Peter Carmeliet.
      The dynamic crosstalk between the different components of the tumor microenvironment is critical to determine cancer progression, metastatic dissemination, tumor immunity, and therapeutic responses. Angiogenesis is critical for tumor growth, and abnormal blood vessels contribute to hypoxia and acidosis in the tumor microenvironment. In this hostile environment, cancer and stromal cells have the ability to alter their metabolism in order to support the high energetic demands and favor rapid tumor proliferation. Recent advances have shown that tumor endothelial cell metabolism is reprogrammed, and that targeting endothelial metabolic pathways impacts developmental and pathological vessel sprouting. Therefore, the use of metabolic antiangiogenic therapies to normalize the blood vasculature, in combination with immunotherapies, offers a clinical niche to treat cancer.
    Keywords:  metabolic reprogramming; tumor angiogenesis; tumor endothelial cell metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms231911052
  13. Front Oncol. 2022 ;12 988626
    Metabolite-derived protein modifications modulating oncogenic signaling.
    Yawen Liu, Anke Vandekeere, Min Xu, Sarah-Maria Fendt, Patricia Altea-Manzano.
      Malignant growth is defined by multiple aberrant cellular features, including metabolic rewiring, inactivation of tumor suppressors and the activation of oncogenes. Even though these features have been described as separate hallmarks, many studies have shown an extensive mutual regulatory relationship amongst them. On one hand, the change in expression or activity of tumor suppressors and oncogenes has extensive direct and indirect effects on cellular metabolism, activating metabolic pathways required for malignant growth. On the other hand, the tumor microenvironment and tumor intrinsic metabolic alterations result in changes in intracellular metabolite levels, which directly modulate the protein modification of oncogenes and tumor suppressors at both epigenetic and post-translational levels. In this mini-review, we summarize the crosstalk between tumor suppressors/oncogenes and metabolism-induced protein modifications at both levels and explore the impact of metabolic (micro)environments in shaping these.
    Keywords:  metabolites; oncogenic signaling; post-translational modification; tumor microenvironment; tumor suppressor gene
    DOI:  https://doi.org/10.3389/fonc.2022.988626
  14. Front Immunol. 2022 ;13 962175
    Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4+ T cell differentiation.
    David Martínez-Méndez, Leonor Huerta, Carlos Villarreal.
      Upon antigen stimulation and co-stimulation, CD4+ T lymphocytes produce soluble factors that promote the activity of other immune cells against pathogens or modified tissues; this task must be performed in presence of a variety of environmental cytokines, nutrient, and oxygen conditions, which necessarily impact T cell function. The complexity of the early intracellular processes taking place upon lymphocyte stimulation is addressed by means of a mathematical model based on a network that integrates variable microenvironmental conditions with intracellular activating, regulatory, and metabolic signals. Besides the phenotype subsets considered in previous works (Th1, Th2, Th17, and Treg) the model includes the main early events in differentiation to the T FH phenotype. The model describes how cytokines, nutrients and oxygen availability regulate the differentiation of naïve CD4+ T cells into distinct subsets. Particularly, it shows that elevated amounts of an all-type mixture of effector cytokines under optimal nutrient and oxygen availability conduces the system towards a highly-polarized Th1 or Th2 state, while reduced cytokine levels allow the expression of the Th17, Treg or T FH subsets, or even hybrid phenotypes. On the other hand, optimal levels of an all-type cytokine mixture in combination with glutamine or tryptophan restriction implies a shift from Th1 to Th2 expression, while decreased levels of the Th2-inducing cytokine IL-4 leads to the rupture of the Th1-Th2 axis, allowing the manifestation of different (or hybrid) subsets. Modeling proposes that, even under reduced levels of pro-inflammatory cytokines, the sole action of hypoxia boost Th17 expression.
    Keywords:  CD4+ T cells; hybrid phenotypes; hypoxia; lymphocytes; mathematical model; metabolism; nutrients
    DOI:  https://doi.org/10.3389/fimmu.2022.962175
  15. Front Physiol. 2022 ;13 989793
    NRF2: A crucial regulator for mitochondrial metabolic shift and prostate cancer progression.
    Brigitta Buttari, Marzia Arese, Rebecca E Oberley-Deegan, Luciano Saso, Arpita Chatterjee.
      Metabolic alterations are a common survival mechanism for prostate cancer progression and therapy resistance. Oxidative stress in the cellular and tumor microenvironment dictates metabolic switching in the cancer cells to adopt, prosper and escape therapeutic stress. Therefore, regulation of oxidative stress in tumor cells and in the tumor-microenvironment may enhance the action of conventional anticancer therapies. NRF2 is the master regulator for oxidative stress management. However, the overall oxidative stress varies with PCa clinical stage, metabolic state and therapy used for the cancer. In agreement, the blanket use of NRF2 inducers or inhibitors along with anticancer therapies cause adverse effects in some preclinical cancer models. In this review, we have summarized the levels of oxidative stress, metabolic preferences and NRF2 activity in the different stages of prostate cancer. We also propose condition specific ways to use NRF2 inducers or inhibitors along with conventional prostate cancer therapies. The significance of this review is not only to provide a detailed understanding of the mechanism of action of NRF2 to regulate oxidative stress-mediated metabolic switching by prostate cancer cells to escape the radiation, chemo, or hormonal therapies, and to grow aggressively, but also to provide a potential therapeutic method to control aggressive prostate cancer growth by stage specific proper use of NRF2 regulators.
    Keywords:  Nrf2; cancer progression; metabolism; mitochondria; oxidative stress; prostate cancer; therapy resistance
    DOI:  https://doi.org/10.3389/fphys.2022.989793
  16. Pharmacol Res. 2022 Oct 07. pii: S1043-6618(22)00436-4. [Epub ahead of print] 106490
    Therapeutic targeting of glutamate dehydrogenase 1 that links metabolic reprogramming and Snail-mediated epithelial-mesenchymal transition in drug-resistant lung cancer.
    Qizhi Wang, Ming Wu, Haobin Li, Xin Rao, Luyao Ao, Huan Wang, Lan Yao, Xinyu Wang, Xiaodan Hong, Jun Wang, Jiye Aa, Minjie Sun, Guangji Wang, Jiali Liu, Fang Zhou.
      Acquired drug resistance and epithelial-mesenchymal transition (EMT) mediated metastasis are two highly interacting determinants for non-small-cell lung cancer (NSCLC) prognosis. This study investigated the common mechanisms of drug resistance and EMT from the perspective of metabolic reprogramming, which may offer new ideas to improve anticancer therapy. Acquired resistant cells were found to grow faster and have a greater migratory and invasive capacity than their parent cells. Metabolomics analysis revealed that acquired resistant cells highly relied on glutamine utilization and mainly fluxed into oxidative phosphorylation energy production. Further mechanistic studies screened out glutamate dehydrogenase 1 (GLUD1) as the determinant of glutamine addiction in acquired resistant NSCLC cells, and provided evidence that GLUD1-mediated α-KG production and the accompanying reactive oxygen species (ROS) accumulation primarily triggered migration and invasion by inducing Snail. Pharmacological and genetic interference with GLUD1 in vitro significantly reversed drug resistance and decreased cell migration and invasion capability. Lastly, the successful application of R162, a selective GLUD1 inhibitor, to overcome both acquired resistance and EMT-induced metastasis in vivo, identified GLUD1 as a promising and druggable therapeutic target for malignant progression of NSCLC. Collectively, our study offers a potential strategy for NSCLC therapy, especially for drug-resistant patients with highly expressed GLUD1.
    Keywords:  Drug resistance; Epithelial–mesenchymal transition; Glutamate dehydrogenase 1; Glutamine catabolism; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.phrs.2022.106490
  17. Cells. 2022 Oct 01. pii: 3103. [Epub ahead of print]11(19):
    Reprogramming T-Cell Metabolism for Better Anti-Tumor Immunity.
    Yu Ping, Chunyi Shen, Bo Huang, Yi Zhang.
      T cells play central roles in the anti-tumor immunity, whose activation and differentiation are profoundly regulated by intrinsic metabolic reprogramming. Emerging evidence has revealed that metabolic processes of T cells are generally altered by tumor cells or tumor released factors, leading to crippled anti-tumor immunity. Therefore, better understanding of T cell metabolic mechanism is crucial in developing the next generation of T cell-based anti-tumor immunotherapeutics. In this review, we discuss how metabolic pathways affect T cells to exert their anti-tumor effects and how to remodel the metabolic programs to improve T cell-mediated anti-tumor immune responses. We emphasize that glycolysis, carboxylic acid cycle, fatty acid oxidation, cholesterol metabolism, amino acid metabolism, and nucleotide metabolism work together to tune tumor-reactive T-cell activation and proliferation.
    Keywords:  T cell; T cell metabolism; anti-tumor function; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells11193103
  18. Cells. 2022 Sep 22. pii: 2956. [Epub ahead of print]11(19):
    Therapeutic Drug-Induced Metabolic Reprogramming in Glioblastoma.
    Trang T T Nguyen, Enyuan Shang, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin.
      Glioblastoma WHO IV (GBM), the most common primary brain tumor in adults, is a heterogenous malignancy that displays a reprogrammed metabolism with various fuel sources at its disposal. Tumor cells primarily appear to consume glucose to entertain their anabolic and catabolic metabolism. While less effective for energy production, aerobic glycolysis (Warburg effect) is an effective means to drive biosynthesis of critical molecules required for relentless growth and resistance to cell death. Targeting the Warburg effect may be an effective venue for cancer treatment. However, past and recent evidence highlight that this approach may be limited in scope because GBM cells possess metabolic plasticity that allows them to harness other substrates, which include but are not limited to, fatty acids, amino acids, lactate, and acetate. Here, we review recent key findings in the literature that highlight that GBM cells substantially reprogram their metabolism upon therapy. These studies suggest that blocking glycolysis will yield a concomitant reactivation of oxidative energy pathways and most dominantly beta-oxidation of fatty acids.
    Keywords:  TCA cycle; glioblastoma; glycolysis; metabolism; oxidative phosphorylation (OXPHOS)
    DOI:  https://doi.org/10.3390/cells11192956
  19. Front Mol Biosci. 2022 ;9 991188
    The metabolic plasticity of B cells.
    Yurena Vivas-García, Alejo Efeyan.
      The humoral response requires rapid growth, biosynthetic capacity, proliferation and differentiation of B cells. These processes involve profound B-cell phenotypic transitions that are coupled to drastic changes in metabolism so as to meet the extremely different energetic requirements as B cells switch from resting to an activated, highly proliferative state and to plasma or memory cell fates. Thus, B cells execute a multi-step, energetically dynamic process of profound metabolic rewiring from low ATP production to transient and large increments of energy expenditure that depend on high uptake and consumption of glucose and fatty acids. Such metabolic plasticity is under tight transcriptional and post-transcriptional regulation. Alterations in B-cell metabolism driven by genetic mutations or by extrinsic insults impair B-cell functions and differentiation and may underlie the anomalous behavior of pathological B cells. Herein, we review molecular switches that control B-cell metabolism and fuel utilization, as well as the emerging awareness of the impact of dynamic metabolic adaptations of B cells throughout the different phases of the humoral response.
    Keywords:  B-cell activation; Oxphos; anabolism; glycolysis; humoral response; metabolic plasticity
    DOI:  https://doi.org/10.3389/fmolb.2022.991188
  20. Biomed Pharmacother. 2022 Oct 10. pii: S0753-3322(22)01145-3. [Epub ahead of print]156 113756
    Ginsenosides in cancer: A focus on the regulation of cell metabolism.
    Wang Yao, Yunfeng Guan.
      Metabolic alterations play a key role in promoting tumor initiation and progression, leading to extensive tumor heterogeneity and adaptability. Thus, targeting abnormal metabolic processes is a promising novel approach for cancer treatment. Numerous pharmacological studies have indicated that many traditional Chinese medicines possess remarkable antitumor activities. Ginsenosides, the main bioactive ingredients of Panax and other types of ginseng, exert beneficial antitumor effects, in addition to the anti-inflammation, anti-oxidant, and anti-fatigue effects. Recently, considerable attention has been paid to the regulation of cancer cell metabolism by ginsenosides. Here, we summarize the structural characteristics and classification of ginsenosides, their antitumor mechanisms, recent progress and the achievements of ginsenoside research in modulating cancer cell metabolism, including the diverse metabolic processes and their regulatory processes, as well as the opportunities and challenges of strategies targeting metabolic vulnerabilities. This review provides novel perspectives on the potential applications of ginsenosides that exert antitumor effects by reshaping cancer metabolism.
    Keywords:  Antitumor activity; Cancer; Cell metabolism; Ginsenosides; Mechanism
    DOI:  https://doi.org/10.1016/j.biopha.2022.113756
  21. Oncogene. 2022 Oct 10.
    Src: coordinating metabolism in cancer.
    Sara G Pelaz, Arantxa Tabernero.
      Metabolism must be tightly regulated to fulfil the dynamic requirements of cancer cells during proliferation, migration, stemness and differentiation. Src is a node of several signals involved in many of these biological processes, and it is also an important regulator of cell metabolism. Glucose uptake, glycolysis, the pentose-phosphate pathway and oxidative phosphorylation are among the metabolic pathways that can be regulated by Src. Therefore, this oncoprotein is in an excellent position to coordinate and finely tune cell metabolism to fuel the different cancer cell activities. Here, we provide an up-to-date summary of recent progress made in determining the role of Src in glucose metabolism as well as the link of this role with cancer cell metabolic plasticity and tumour progression. We also discuss the opportunities and challenges facing this field.
    DOI:  https://doi.org/10.1038/s41388-022-02487-4
  22. Nat Cell Biol. 2022 Oct 13.
    Metabolic communication in the tumour-immune microenvironment.
    Kung-Chi Kao, Stefania Vilbois, Chin-Hsien Tsai, Ping-Chih Ho.
      The metabolically hostile tumour microenvironment imposes barriers to tumour-infiltrating immune cells and impedes durable clinical remission following immunotherapy. Metabolic communication between cancer cells and their neighbouring immune cells could determine the amplitude and type of immune responses, highlighting a potential involvement of metabolic crosstalk in immune surveillance and escape. In this Review, we explore tumour-immune metabolic crosstalk and discuss potential nutrient-limiting strategies that favour anti-tumour immune responses.
    DOI:  https://doi.org/10.1038/s41556-022-01002-x
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