bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2022–05–15
twenty-two papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Mechanistic basis for the allosteric activation of mitochondrial glutaminase C, a key driver of glutamine metabolism in cancer cells.
  2. Glutamine metabolism co-ordinates the cell-cycle with cell fate in stem cells.
  3. Comprehensive Analysis of Subtypes and Identification of Key lncRNAs Based on Glutamine Metabolism-Related Long Noncoding RNAs.
  4. Circ_0001273 downregulation inhibits the growth, migration and glutamine metabolism of esophageal cancer cells via targeting the miR-622/SLC1A5 signaling axis.
  5. TBK1 participates in glutaminolysis by mediating the phosphorylation of RIPK3 to promote endotoxin tolerance.
  6. Glutamine Counteracts Glucose-Mediated Human Endothelial Cell Dysfunction.
  7. Role of Amino Acid Transporter SNAT1/SLC38A1 in Human Melanoma.
  8. Exploring the Role of Metabolites in Cancer and the Associated Nerve Crosstalk.
  9. Targeting 2-oxoglutarate dehydrogenase for cancer treatment.
  10. Scleraxis is Required for Induction of GLS1 Expression in Cardiac Myofibroblasts.
  11. SLC3A2 N-glycosylation and alternate evolutionary trajectories for amino acid metabolism.
  12. A pan-cancer metabolic atlas of the tumor microenvironment.
  13. Targeting GCN2 Regulation of Amino Acid Homeostasis in Prostate Cancer.
  14. Metabolic outliers in human disease.
  15. Cancer Metabolic Subtypes and Their Association with Molecular and Clinical Features.
  16. Mitochondrial GCN5L1 regulates glutaminase acetylation and hepatocellular carcinoma.
  17. Mitochondrial ROS in Slc4a11 KO Corneal Endothelial Cells Lead to ER Stress.
  18. Polystyrene microplastics up-regulates liver glutamine and glutamate synthesis and promotes autophagy-dependent ferroptosis and apoptosis in the cerebellum through the liver-brain axis.
  19. Long-term outcomes and prognosis for patients with sarcomatoid hepatocellular carcinoma.
  20. Inhibition of Anaplerosis Prevented Mitochondrial Dysfunction and Vascular Remodeling in Pulmonary Hypertension.
  21. Metabolic oscillations during cell-cycle progression.
  22. Investigating the therapeutic efficacy of a novel mTORC1 inhibitor, RMC-6272, on liver tumors with b-catenin activation.
  1. FASEB J. 2022 May;36 Suppl 1
    Mechanistic basis for the allosteric activation of mitochondrial glutaminase C, a key driver of glutamine metabolism in cancer cells.
    Thuy-Tien T Nguyen, Sekar Ramachandran, Matthew J Hill, Richard A Cerione.
      The dependence of cancer cells on glutamine metabolism, the most abundant amino acid in plasma, has been observed in many highly aggressive and deadly cancers including pancreatic cancer, triple-negative breast cancer, and glioblastoma. The mitochondrial enzyme glutaminase C (GAC) catalyzes the hydrolysis of glutamine to glutamate, the first step in glutamine metabolism, highlighting GAC as a potentially important therapeutic target. GAC acquires maximal catalytic activity upon binding to anionic activators like inorganic phosphate. To delineate the mechanism of GAC activation, we used the tryptophan substitution of tyrosine 466 in the catalytic site of the enzyme as a fluorescence reporter for glutamine binding in the presence and absence of phosphate. We show that in the absence of phosphate, glutamine binding to the GAC (Y466W) tetramer exhibits positive cooperativity. A high-resolution X-ray structure of tetrameric GAC (Y466W) bound to glutamine suggests that cooperativity in substrate binding is coupled to tyrosine 249, located at the edge of the catalytic site (i.e. designated the 'lid'), adopting two distinct conformations. In one dimer within the GAC tetramer, the lids are open and glutamine binds weakly, whereas, in the adjoining dimer, the lids are closed over the substrates resulting in higher affinity interactions. When crystallized in the presence of glutamine and phosphate, all four subunits of the GAC (Y466W) tetramer have bound glutamine with closed lids. Glutamine now binds with high affinity to each subunit, which then undergo simultaneous catalysis. These findings show how the regulated transitioning of GAC between different conformational states ensures maximal catalytic activity is reached in cancer cells only when an allosteric activator is available.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R2820
  2. FASEB J. 2022 May;36 Suppl 1
    Glutamine metabolism co-ordinates the cell-cycle with cell fate in stem cells.
    Chinan Kikani, Michael Xiao.
      Activation of stem cell proliferation is a critical event in tissue regeneration. The metabolic switch in adult stem cells from the oxidative to the glycolytic mode of carbon utilization is essential for rapid proliferative bursts, but its impact on self-renewal is unclear. During the glycolytic mode of glucose utilization, glutamine-derived carbons drive the mitochondrial TCA cycle. While glutamine is required for stem cell proliferation burst, its role in maintaining stem cell self-renewal property remains unclear. Here, we show that withdrawal or chemical inhibition of mitochondrial glutamine metabolism blunted adult muscle stem cell proliferation, but also reactivated the transcription of self-renewal-associated transcripts, such as Pax7, to reduce stem cell heterogeneity and build the self-renewing stem cell population. Thus, surprisingly, glutamine withdrawal preserved and accentuated the self-renewing stem cell population. This effect of glutamine is mediated via reductive carboxylation of alpha-ketoglutarate. Mechanistically, we extensively show that glutamine inhibited cell-cycle linked self-renewing network during the G2-M phase of cell-cycle to drive the exit from self-renewal during the terminal mitosis phase before differentiation. Thus, we propose that glutamine metabolism plays an unexpected role in building the progenitor population that is uniquely primed for differentiation during tissue regeneration.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.0R345
  3. Comput Math Methods Med. 2022 ;2022 2807354
    Comprehensive Analysis of Subtypes and Identification of Key lncRNAs Based on Glutamine Metabolism-Related Long Noncoding RNAs.
    Yuwei Feng, Xiaowei Sun, Tiangu Yang, Jingqi Han, Dapeng Zhou, Haitao Ren, Yulong Sheng, Yanhua Wang.
       Background: Long noncoding RNAs (lncRNAs) are becoming a critical class of metabolic regulate molecule in cancer. Glutamine is a regulator that contributes to each of the core metabolic tasks in proliferating tumor cells. Thus, we aimed to evaluate the association of lncRNAs with glutamine metabolism in lung adenocarcinoma (LUAD).
    Methods: Using single-sample gene set enrichment analysis (ssGSEA), LUAD specimens were assigned scores based on glutamine metabolism-related genes, and the shared common glutamine metabolism-related lncRNAs in three different LUAD data cohorts were identified. ConsensusClusterPlus was used to perform unsupervised clustering analysis in patients with LUAD. Key glutamine metabolism-related lncRNAs were identified by first-order partial correlation analysis.
    Results: A total of 11 shared glutamine metabolism-associated lncRNAs were identified in three LUAD data cohorts, and LUAD patients were classified into three glutamine metabolism subtypes based on the expressions of the related genes. C1 exhibited shorter overall survival (OS), poor genomic instability, and inadequate infiltration of immune cell types in the tumor microenvironment (TME) and was representative of the immunodeficiency phenotype. C2 represented the immunosuppressive phenotype while C3 represented the immune activation phenotype, exhibiting the highest sensitivity to immunotherapy. Nine of the 11 lncRNAs were localized to the nucleus. Finally, three key lncRNAs, significantly enriched in multiple metabolic pathways, were screened and found to be remarkably related to the OS of LUAD.
    Conclusion: We identified three glutamine metabolism subtypes of LUAD, which reflected different OS, genomic, and TME features, and identified three key glutamine metabolism-associated lncRNAs may contribute to further study of lncRNAs in cancer metabolism.
    DOI:  https://doi.org/10.1155/2022/2807354
  4. Thorac Cancer. 2022 May 13.
    Circ_0001273 downregulation inhibits the growth, migration and glutamine metabolism of esophageal cancer cells via targeting the miR-622/SLC1A5 signaling axis.
    Bomeng Wu, Ying Chen, Ying Chen, Xihao Xie, Hanping Liang, Fengyuan Peng, Weibi Che.
       BACKGROUND: Esophageal cancer is a relatively rare cancer. However, its death rate is not to be taken lightly. Accumulating evidence indicates circular RNA (circRNA) is implicated in cancer development. The objective of this study was to unveil the role of circ_0001273 in esophageal cancer (EC).
    METHODS: For expression analysis of circ_0001273, miR-622 and solute carrier family 1 member 5 (SLC1A5), quantitative real-time PCR (qPCR) and Western blot were conducted. Cell proliferation was evaluated by cell counting kit-8 (CCK-8), EdU and colony formation assays. Cell apoptosis and cell migration were investigated using flow cytometry assay and wound healing assay. Glutamine metabolism was assessed by glutamine consumption and glutamate production using matched kits. The predicted binding relationship between miR-622 and circ_0001273 or SLC1A5 was validated by dual-luciferase reporter assay. An in vivo xenograft model was established to determine the role of circ_0001273 on tumor growth.
    RESULTS: Circ_0001273 was upregulated in EC tumor tissues and cells. Knockdown of circ_0001273 repressed EC cell proliferation, migration, epithelial-mesenchymal transition (EMT) and glutamine metabolism. Circ_0001273 knockdown also blocked tumor development in animal models. MiR-622 was targeted by circ_0001273, and its inhibition reversed the functional effects of circ_0001273 knockdown. SLC1A5 was a target gene of miR-622, and circ_0001273 targeted miR-622 to positively regulate SLC1A5 expression. The inhibitory effects of miR-622 enrichment on EC cell proliferation, migration, EMT and glutamine metabolism were recovered by SLC1A5 overexpression.
    CONCLUSION: Circ_0001273 high expression contributed to EC progression via modulating the miR-622/SLC1A5 signaling axis.
    Keywords:  SLC1A5; circ_0001273; esophageal cancer; miR-622
    DOI:  https://doi.org/10.1111/1759-7714.14458
  5. Mol Immunol. 2022 May 06. pii: S0161-5890(22)00195-X. [Epub ahead of print]147 101-114
    TBK1 participates in glutaminolysis by mediating the phosphorylation of RIPK3 to promote endotoxin tolerance.
    Lehan Pan, Lian Yang, Zhujun Yi, Wenfeng Zhang, Jianping Gong.
      TRAF-associated NF-κB activator (TANK)-binding kinase 1 (TBK1), a nonclassical IκB kinase (IKK), and its effect on inflammation have not been entirely clarified. Here, we identified that TBK1 participates in the catabolism of glutamine by mediating the phosphorylation of receptor-interacting protein kinase 3 (RIPK3) and promoting macrophage endotoxin tolerance (ET). We found that the TBK1 protein directly interacts with the RIPK3 protein and mediates the phosphorylation of RIPK3 in macrophages. Activated RIPK3 can directly bind to glutamate dehydrogenase 1 (GLUD1), which is known to be a critical enzyme for catalyzing glutamine decomposition, to improve its catalytic activity and increase the production of α-ketoglutarate (α-KG) in macrophages. α-KG generated from glutaminolysis can promote M2 activation and restrict M1 polarization, which plays a crucial role in promoting lipopolysaccharide (LPS)-induced ET. As a result of TBK1 regulating the phosphorylation level of RIPK3, overexpressed TBK1 could enhance the tolerance of macrophages to endotoxin through glutaminolysis. Overall, these findings reveal a novel mechanism for the metabolic control of inflammation and for the induction of ET by modulating glutamine metabolism.
    Keywords:  Endotoxin tolerance; GLUD1; RIPK3; Sepsis; TBK1; α-KG
    DOI:  https://doi.org/10.1016/j.molimm.2022.04.009
  6. FASEB J. 2022 May;36 Suppl 1
    Glutamine Counteracts Glucose-Mediated Human Endothelial Cell Dysfunction.
    William Durante, Kelly J Peyton.
      Vascular disease is the major cause of morbidity and mortality in diabetes mellitus. While the etiology of vascular disease is multifactorial, endothelial cell (EC) dysfunction is a hallmark of diabetes-associated vascular disease. Substantial evidence indicates that high glucose (HG) concentrations trigger EC dysfunction through the production of reactive oxygen species (ROS). Recently, studies from our laboratory and others identified the conditionally essential amino acid glutamine as a critical regulator of oxidative stress and EC phenotype. In the present study, we investigated the effect of HG concentrations on ECs and determined if glutamine influences the biological actions of HG in these cells. Treatment of human umbilical vein ECs with glucose (5.6-25mM) resulted in a concentration- and time-dependent increase in the production of reactive oxygen species (ROS), whereas mannitol (an osmotic control) minimally affected ROS formation. HG concentrations (25mM) also evoked a time-dependent decrease in EC viability that was paralleled by an increase in apoptosis, as reflected by a rise in annexin V binding and caspase-3 activity. Notably, the administration of glutamine (500μM) inhibits HG-mediated endothelial ROS production and improves EC viability in response to HG levels. Glutamine also induces the expression of heme oxygenase-1 (HO-1) in ECs. However, pharmacological inhibition of HO-1 activity with tin protoporphyrin-IX (10μM) reversed the antioxidant and cytoprotective effect of glutamine in HG-treated ECs. In conclusion, the present study found that glutamine counteracts HG concentration-mediated ROS generation and EC death. Moreover, it demonstrates that the induction of HO-1 by glutamine contributes to the beneficial actions of the amino acid and identifies glutamine as a critical regulator of EC survival in diabetes.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R4921
  7. Cancers (Basel). 2022 Apr 26. pii: 2151. [Epub ahead of print]14(9):
    Role of Amino Acid Transporter SNAT1/SLC38A1 in Human Melanoma.
    Ines Böhme-Schäfer, Sandra Lörentz, Anja Katrin Bosserhoff.
      The tumor metabolism is an important driver of cancer cell survival and growth, as rapidly dividing tumor cells exhibit a high demand for energetic sources and must adapt to microenvironmental changes. Therefore, metabolic reprogramming of cancer cells and the associated deregulation of nutrient transporters are a hallmark of cancer cells. Amino acids are essential for cancer cells to synthesize the necessary amount of protein, DNA, and RNA. Although cancer cells can synthesize glutamine de novo, most cancer cells show an increased uptake of glutamine from the tumor microenvironment. Especially SNAT1/SLC38A1, a member of the sodium neutral amino acid transporter (SNAT) family, plays an essential role during major net import of glutamine. In this study, we revealed a significant upregulation of SNAT1 expression in human melanoma tissue in comparison to healthy epidermis and an increased SNAT1 expression level in human melanoma cell lines when compared to normal human melanocytes (NHEMs). We demonstrated that functional inhibition of SNAT1 with α-(methylamino) isobutyric acid (MeAIB), as well as siRNA-mediated downregulation reduces cancer cell growth, cellular migration, invasion, and leads to induction of senescence in melanoma cells. Consequently, these results demonstrate that the amino acid transporter SNAT1 is essential for cancer growth, and indicates a potential target for cancer chemotherapy.
    Keywords:  amino acid transporter; melanoma; tumor metabolism
    DOI:  https://doi.org/10.3390/cancers14092151
  8. Nutrients. 2022 Apr 21. pii: 1722. [Epub ahead of print]14(9):
    Exploring the Role of Metabolites in Cancer and the Associated Nerve Crosstalk.
    Inah Gu, Emory Gregory, Casey Atwood, Sun-Ok Lee, Young Hye Song.
      Since Otto Warburg's first report on the increased uptake of glucose and lactate release by cancer cells, dysregulated metabolism has been acknowledged as a hallmark of cancer that promotes proliferation and metastasis. Over the last century, studies have shown that cancer metabolism is complex, and by-products of glucose and glutamine catabolism induce a cascade of both pro- and antitumorigenic processes. Some vitamins, which have traditionally been praised for preventing and inhibiting the proliferation of cancer cells, have also been proven to cause cancer progression in a dose-dependent manner. Importantly, recent findings have shown that the nervous system is a key player in tumor growth and metastasis via perineural invasion and tumor innervation. However, the link between cancer-nerve crosstalk and tumor metabolism remains unclear. Here, we discuss the roles of relatively underappreciated metabolites in cancer-nerve crosstalk, including lactate, vitamins, and amino acids, and propose the investigation of nutrients in cancer-nerve crosstalk based on their tumorigenicity and neuroregulatory capabilities. Continued research into the metabolic regulation of cancer-nerve crosstalk will provide a more comprehensive understanding of tumor mechanisms and may lead to the identification of potential targets for future cancer therapies.
    Keywords:  amino acid metabolism; cancer; cancer–nerve crosstalk; lactate; metabolites; perineural invasion; tumor innervation; vitamins
    DOI:  https://doi.org/10.3390/nu14091722
  9. Am J Cancer Res. 2022 ;12(4): 1436-1455
    Targeting 2-oxoglutarate dehydrogenase for cancer treatment.
    Ling-Chu Chang, Shih-Kai Chiang, Shuen-Ei Chen, Mien-Chie Hung.
      Tricarboxylic acid (TCA) cycle, also called Krebs cycle or citric acid cycle, is an amphoteric pathway, contributing to catabolic degradation and anaplerotic reactions to supply precursors for macromolecule biosynthesis. Oxoglutarate dehydrogenase complex (OGDHc, also called α-ketoglutarate dehydrogenase) a highly regulated enzyme in TCA cycle, converts α-ketoglutarate (αKG) to succinyl-Coenzyme A in accompany with NADH generation for ATP generation through oxidative phosphorylation. The step collaborates with glutaminolysis at an intersectional point to govern αKG levels for energy production, nucleotide and amino acid syntheses, and the resources for macromolecule synthesis in cancer cells with rapid proliferation. Despite being a flavoenzyme susceptible to electron leakage contributing to mitochondrial reactive oxygen species (ROS) production, OGDHc is highly sensitive to peroxides such as HNE (4-hydroxy-2-nonenal) and moreover, its activity mediates the activation of several antioxidant pathways. The characteristics endow OGDHc as a critical redox sensor in mitochondria. Accumulating evidences suggest that dysregulation of OGDHc impairs cellular redox homeostasis and disturbs substrate fluxes, leading to a buildup of oncometabolites along the pathogenesis and development of cancers. In this review, we describe molecular interactions, regulation of OGDHc expression and activity and its relationships with diseases, specifically focusing on cancers. In the end, we discuss the potential of OGDHs as a therapeutic target for cancer treatment.
    Keywords:  2-oxoglutarate dehydrogenase; cancer metabolism; reactive oxygen species; tricarboxylic acid cycle; α-ketoglutarate dehydrogenase complex
  10. FASEB J. 2022 May;36 Suppl 1
    Scleraxis is Required for Induction of GLS1 Expression in Cardiac Myofibroblasts.
    Sikta Chattopadhyaya, Raghu S Nagalingam, Pavit Narhan, Dayna A Ledingham, Teri L Moffatt, Michael P Czubryt.
      Cardiac fibrosis is an aberrant wound healing process involving excessive production of extracellular matrix proteins resulting in impaired systolic and diastolic function of the heart, contributing to heart failure and death. Glutaminolysis, which involves conversion of glutamine to glutamate by glutaminase (GLS), and conversion of glutamate to α-ketoglutarate to fuel oxidative metabolism via the tricarboxylic acid cycle, has been reported as a mechanism for meeting the energy demand required for pulmonary and liver fibrosis however its contribution in cardiac fibrosis is unclear. Although the role of the transcription factor Scleraxis has been established in the phenotypic conversion of cardiac fibroblasts to fibrotic myofibroblasts by our lab, Scleraxis' role in glutaminolysis remains unelucidated. Our results here show Scleraxis expression was increased by 9 fold and GLS1 by 4 fold when comparing freshly isolated rat cardiac fibroblasts to fibrogenic myofibroblasts. While Scleraxis overexpression increased GLS1 expression 20-fold, Scleraxis knockdown attenuated GLS1 expression by 76% in cardiac myofibroblasts while cardiac fibroblasts from Scleraxis knockout mice exhibited a 90% loss of GLS1 expression. TGFβ, one of the primary inducers of cardiac fibrosis induces enhanced expression of Scleraxis and has been found to be highly dependent on Scleraxis for many of its downstream effects. TGFβ treatment of activated cardiac fibroblasts from wild type mice doubled the expression of GLS1, but failed to induce GLS1 expression in Scleraxis knockout cells. Via luciferase assay we found a dose-dependent transactivation of the human GLS1 promoter by Scleraxis in NIH3T3 fibroblasts. While Scleraxis significantly transactivated the hGLS1 promoter, mutation of an E-Box Scleraxis putative binding site caused 70% attenuation of promoter transactivation. These findings suggest that Scleraxis is sufficient and required to regulate GLS1 expression to facilitate increased energy metabolism during cardiac fibroblast to myofibroblast conversion.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R2313
  11. FASEB J. 2022 May;36 Suppl 1
    SLC3A2 N-glycosylation and alternate evolutionary trajectories for amino acid metabolism.
    James W Dennis, Cunjie Zhang, Judy Pawling, Geoff G Hesketh, Eselle Dransart, Massiullah Shafaq-Zahah, Linda Z Penn, Anne-Claude Gingras, Ludger Johannes.
      Cancer and other proliferative diseases are driven by cooperative rewiring of growth signaling and metabolism, where posttranslational modifications to proteins play a critical role in maintaining the disease state. Most PTMs require metabolites as donor substrates, providing underappreciated link between metabolism and signaling. Protein N-glycosylation and Golgi remodeling of N-glycan on receptor kinases, T cell receptor, glucagon receptor, and glucose transporters provides feedback between signaling and metabolism. In turn, N-glycosylation requires uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), generated by the hexosamine biosynthesis pathway (HBP) from glucose, glutamine and acetyl-CoA, where the flux of these substrates into UDP-GlcNAc are in competition with glycolysis, glutaminolysis and fatty-acid turnover. Thus, N-glycan branching, a pathway of N-acetylglucosaminyltransferases (MGAT1, 2, 4 and 5, avian 6) in the Golgi, is a sensor of central metabolism. In a search for additional glycoproteins that link metabolism, N-glycosylation and signaling, we identified SLC3A2 (4F2hc, CD98),an adaptor to amino acid (AA) transporters SLC7A5-11, -13 which stabilizes cell surface residency. The SLC3A2*SLC7A5 exchanger imports essential AA that stimulate mTOR signaling and anabolic metabolism, while SLC3A2*SLC7A11 supports glutathione synthesis and mitigation of oxidative stress. Analysis of SLC3A2 N-glycans revealed stable site-specific profiles of Golgi remodeling, with the exception of the conserved N365 where branching and poly-N-acetyllactosamine content were sensitive to the insertion of lost ancestral sites and to HBP. The N-glycans are positioned to promote galectin-mediated clustering with N-glycosylated Na++ /AA symporters and enhance diffusion-limited flux between exchangers and AA /Na+ symporters. In a successful experiment of Nature, SLC3A2 has been deleted in Neoaves, a clade representing 95% of Ave species that are adapted for flapping flight, the most metabolically intense form of vertebrate locomotion. Neoaves have also acquired a unique N-glycan branching specificity GnT-VI (Mgat6, Q9DGD1), which may support an alternate clustering of N-glycosylated transporters. KEAP1, and four SLC7A family exchangers are also absent, and two others have duplicated, consistent with a shift in metabolic imperatives of Neoaves. The fate of these genes in Primates, Neoaves and Naked mole rat highlights the tension between metabolic rates and oxidative stress that govern lifestyle and longevity.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.0I108
  12. Cell Rep. 2022 May 10. pii: S2211-1247(22)00567-8. [Epub ahead of print]39(6): 110800
    A pan-cancer metabolic atlas of the tumor microenvironment.
    Neha Rohatgi, Umesh Ghoshdastider, Probhonjon Baruah, Tanmay Kulshrestha, Anders Jacobsen Skanderup.
      Tumors are heterogeneous cellular environments with entwined metabolic dependencies. Here, we use a tumor transcriptome deconvolution approach to profile the metabolic states of cancer and non-cancer (stromal) cells in bulk tumors of 20 solid tumor types. We identify metabolic genes and processes recurrently altered in cancer cells across tumor types, highlighting pan-cancer upregulation of deoxythymidine triphosphate (dTTP) production. In contrast, the tryptophan catabolism rate-limiting enzymes IDO1 and TDO2 are highly overexpressed in stroma, raising the hypothesis that kynurenine-mediated suppression of antitumor immunity may be predominantly constrained by the stroma. Oxidative phosphorylation is the most upregulated metabolic process in cancer cells compared to both stromal cells and a large atlas of cancer cell lines, suggesting that the Warburg effect may be less pronounced in cancer cells in vivo. Overall, our analysis highlights fundamental differences in metabolic states of cancer and stromal cells inside tumors and establishes a pan-cancer resource to interrogate tumor metabolism.
    Keywords:  CP: Cancer; CP: Metabolism; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2022.110800
  13. FASEB J. 2022 May;36 Suppl 1
    Targeting GCN2 Regulation of Amino Acid Homeostasis in Prostate Cancer.
    Ricardo Cordova, Jagannath Misra, Parth H Amin, Nur P Damayanti, Kenneth R Carlson, Angela J Klunk, Emily T Mirek, Marcus J Miller, Tracy G Anthony, Roberto Pili, Ronald C Wek, Kirk A Staschke.
      The Integrated Stress Response (ISR) plays a critical role in the adaptation and survival of tumor cells to exogenous and endogenous stresses. The ISR features four protein kinases (PERK, GCN2, PKR, and HRI), each activated by different stresses, that phosphorylate the eukaryotic translation initiation factor eIF2, resulting in repression of global protein synthesis. Paradoxically, eIF2 phosphorylation also enhances translation of select gene transcripts, including the transcription factor ATF4, which is central for ISR-directed gene transcription. Therefore, the ISR directs translational and transcriptional control that is critical for cancer stress adaptation. Moreover, eIF2 phosphorylation and ATF4 have recently been suggested to play a role in prostate cancer (PCa) growth and survival; however, the specific function of ISR kinases, their mode of activation, and the mechanisms by which the ISR facilitate PCa progression are unknown. We discovered that GCN2 is activated in a range of PCa cell lines, contributing to enhanced eIF2 phosphorylation and ATF4 expression. Genetic or pharmacological inhibition of GCN2 reduces growth in androgen-sensitive and castration-resistant PCa cell lines in culture and cell line-derived and patient-derived xenograft mouse models in vivo. Induction of GCN2 is accompanied by limitations of select amino acids and accumulation of cognate tRNAs that are reported to be activators of GCN2. A transcriptome analysis of PCa cells treated with a specific GCN2 small molecular inhibitor indicates that GCN2 is critical for expression of SLCgenes involved in metabolite transport. We found that GCN2 inhibition decreases intracellular amino acid levels accounting for reduced growth in PCa cells. Using CRISPR-based phenotypic screens and genome-wide gene expression analyses of wild-type and GCN2-depleted PCa cells, we confirmed the importance of the transporter genes in PCa fitness. One transporter, SLC3A2 (4F2), is induced by GCN2 and is essential for PCa proliferation. SLC3A2 engages with many nutrient transporters, allowing for their localization to the plasma membrane. Importantly, expression of SLC3A2 reduced GCN2 activation and rescued decreased amino acid levels and growth inhibition due to loss of GCN2. Our results indicate that select amino acid limitations activate GCN2 in PCa, resulting in the upregulation of key amino acid transporters, including 4F2 (SLC3A2), which provide for nutrient import to facilitate protein synthesis and metabolism required for PCa progression. We conclude that GCN2 and the ISR are promising therapeutic targets for both androgen-sensitive and castration-resistant prostate cancer.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.0R314
  14. FASEB J. 2022 May;36 Suppl 1
    Metabolic outliers in human disease.
    Ralph DeBerardinis.
      Many human diseases are caused by mutations that perturb metabolism at the cellular level and result in tissue dysfunction. Some metabolic perturbations result in disease by interrupting the canonical functions of the metabolic network: producing energy, generating precursors for macromolecular synthesis, maintaining redox balance, disposing of waste, etc. Others interfere with processes beyond the conventional metabolic network, interfering with signaling and gene expression networks. Understanding these pathological states of metabolic perturbation may help us develop rational approaches to normalize metabolism and restore health. We study two types of diseases characterized by metabolic dysfunction: inborn errors of metabolism and cancer. I will discuss ongoing work in these diseases that seeks to characterize abnormal metabolic states directly in human subjects, then uses experimental models to explore disease mechanisms and propose potential therapies. I will emphasize methods in metabolomics and stable isotope tracing that allow us observe metabolic phenotypes in intact systems relevant to physiology and disease, highlighting recent work on tumor metabolism in patients and genetically-defined metabolic anomalies that interfere with mammalian developmental programs.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.0I180
  15. Cancers (Basel). 2022 Apr 25. pii: 2145. [Epub ahead of print]14(9):
    Cancer Metabolic Subtypes and Their Association with Molecular and Clinical Features.
    Enrico Moiso, Paolo Provero.
      The alterations of metabolic pathways in cancer have been investigated for many years, beginning long before the discovery of the role of oncogenes and tumor suppressors, and the last few years have witnessed renewed interest in this topic. Large-scale molecular and clinical data on tens of thousands of samples allow us to tackle the problem from a general point of view. Here, we show that transcriptomic profiles of tumors can be exploited to define metabolic cancer subtypes, which can be systematically investigated for associations with other molecular and clinical data. We find thousands of significant associations between metabolic subtypes and molecular features such as somatic mutations, structural variants, epigenetic modifications, protein abundance and activation, and with clinical/phenotypic data, including survival probability, tumor grade, and histological types, which we make available to the community in a dedicated web resource. Our work provides a methodological framework and a rich database of statistical associations, which will contribute to the understanding of the role of metabolic alterations in cancer and to the development of precision therapeutic strategies.
    Keywords:  cancer metabolism; computational biology; genomics
    DOI:  https://doi.org/10.3390/cancers14092145
  16. Clin Transl Med. 2022 May;12(5): e852
    Mitochondrial GCN5L1 regulates glutaminase acetylation and hepatocellular carcinoma.
    Taotao Zhang, Yunlong Cui, Yanjin Wu, Jiahui Meng, Linmeng Han, Jiaqi Zhang, Chunyu Zhang, Chenxi Yang, Lu Chen, Xue Bai, Kai Zhang, Kaiyuan Wu, Michael N Sack, Lingdi Wang, Lu Zhu.
       BACKGROUND: Glutaminolysis is a critical metabolic process that promotes cancer cell proliferation, including hepatocellular carcinoma (HCC). Delineating the molecular control of glutaminolysis could identify novel targets to ameliorate this oncogenic metabolic pathway. Here, we evaluated the role of general control of amino acid synthesis 5 like 1 (GCN5L1), a regulator of mitochondrial protein acetylation, in modulating the acetylation and activity of glutaminase to regulate HCC development.
    METHODS: Cell proliferation was determined by MTT, 2D and soft agar clone formation assays and orthotopic tumour assays in nude mice. GLS1/2 acetylation and activities were measured in cells and tumours to analyse the correlation with GCN5L1 expression and mTORC1 activation.
    RESULTS: Hepatic GCN5L1 ablation in mice markedly increased diethylnitrosamine (DEN)-induced HCC, and conversely, the transduction of mitochondrial-restricted GCN5L1 protected wild-type mice against HCC progression in response to DEN and carbon tetrachloride (CCl4 ) exposure. GCN5L1-depleted HepG2 hepatocytes enhanced tumour growth in athymic nude mice. Mechanistically, GCN5L1 depletion promoted cell proliferation through mTORC1 activation. Interestingly, liver-enriched glutaminase 2 (GLS2) appears to play a greater role than ubiquitous and canonical tumour-enriched glutaminase 1 (GLS1) in promoting murine HCC. Concurrently, GCN5L1 promotes acetylation and inactivation of both isoforms and increases enzyme oligomerisation. In human HCC tumours compared to adjacent tissue, there were variable levels of mTORC1 activation, GCN5L1 levels and glutaminase activity. Interestingly, the levels of GCN5L1 inversely correlated with mTORC1 activity and glutaminase activity in these tumours.
    CONCLUSIONS: Our study identified that glutaminase activity, rather than GLS1 or GLS2 expression, is the key factor in HCC development that activates mTORC1 and promotes HCC. In the Kaplan-Meier analysis of liver cancer, we found that HCC patients with high GCN5L1 expression survived longer than those with low GCN5L1 expression. Collectively, GCN5L1 functions as a tumour regulator by modulating glutaminase acetylation and activity in the development of HCC.
    Keywords:  GCN5L1; HCC; glutaminase; mTORC1; mitochondria acetylation
    DOI:  https://doi.org/10.1002/ctm2.852
  17. Front Cell Dev Biol. 2022 ;10 878395
    Mitochondrial ROS in Slc4a11 KO Corneal Endothelial Cells Lead to ER Stress.
    Rajalekshmy Shyam, Diego G Ogando, Joseph A Bonanno.
      Recent studies from Slc4a11 -/- mice have identified glutamine-induced mitochondrial dysfunction as a significant contributor toward oxidative stress, impaired lysosomal function, aberrant autophagy, and cell death in this Congenital Hereditary Endothelial Dystrophy (CHED) model. Because lysosomes are derived from endoplasmic reticulum (ER)-Golgi, we asked whether ER function is affected by mitochondrial ROS in Slc4a11 KO corneal endothelial cells. In mouse Slc4a11 -/- corneal endothelial tissue, we observed the presence of dilated ER and elevated expression of ER stress markers BIP and CHOP. Slc4a11 KO mouse corneal endothelial cells incubated with glutamine showed increased aggresome formation, BIP and GADD153, as well as reduced ER Ca2+ release as compared to WT. Induction of mitoROS by ETC inhibition also led to ER stress in WT cells. Treatment with the mitochondrial ROS quencher MitoQ, restored ER Ca2+ release and relieved ER stress markers in Slc4a11 KO cells in vitro. Systemic MitoQ also reduced BIP expression in Slc4a11 KO endothelium. We conclude that mitochondrial ROS can induce ER stress in corneal endothelial cells.
    Keywords:  ERAD (ER associated protein degradation); MitoQ; ROS—reactive oxygen species; SLC4A11 ammonia transporter; corneal endothelial cells; er stress
    DOI:  https://doi.org/10.3389/fcell.2022.878395
  18. Environ Pollut. 2022 May 09. pii: S0269-7491(22)00663-7. [Epub ahead of print] 119449
    Polystyrene microplastics up-regulates liver glutamine and glutamate synthesis and promotes autophagy-dependent ferroptosis and apoptosis in the cerebellum through the liver-brain axis.
    Kai Yin, Dongxu Wang, Hongjing Zhao, Yu Wang, Yue Zhang, Yachen Liu, Baoying Li, Mingwei Xing.
      Microplastics (MPs), which are emerging environmental pollutants, remain uncertainties in their toxic mechanism. MPs have been linked to severe liver metabolic disorders and neurotoxicity, but it is still unknown whether the abnormal metabolites induced by MPs can affect brain tissue through the liver-brain axis. Exposed to MPs of chickens results in liver metabolic disorders and increased glutamine and glutamate synthesis. The relative expression of glutamine in the C group was -0.862, the L-PS group was 0.271, and the H-PS group was 0.592. The expression of tight junction proteins in the blood-brain barrier (BBB) was reduced by PS-MPs. Occludin protein expression decreased by 35.8%-41.2%. Claudin 3 decreased by 19.6%-42.3%, and ZO-1 decreased by 28.3%-44.6%. Excessive glutamine and glutamate cooperated with PS-MPs to inhibit the Nrf2-Keap1-HO-1/NQO1 signaling pathway and triggered autophagy-dependent ferroptosis and apoptosis. GPX protein expression decreased by 30.9%-38%. LC3II/LC3I increased by 54%, and Caspase 3 increased by 45%. Eventually, the number of Purkinje cells was reduced, causing neurological dysfunction. In conclusion, this study provides new insights for revealing the mechanism of nervous system damaged caused by PS-MPs exposed in chickens.
    Keywords:  Cerebellum; Ferroptosis; Glutamine; Liver-brain axis; Microplastic
    DOI:  https://doi.org/10.1016/j.envpol.2022.119449
  19. Ann Transl Med. 2022 Apr;10(7): 394
    Long-term outcomes and prognosis for patients with sarcomatoid hepatocellular carcinoma.
    Cheng Zhou, Xin Zhang, Kaiqian Zhou, Yingyong Hou, Feiyu Chen, Xiangyu Zhang, Yuan Ji, Shuangjian Qiu, Jia Fan, Jian Zhou, Yuhong Zhou, Zheng Wang.
       Background: Characterized by spindle cell composition in hepatocellular carcinoma tumor, sarcomatoid hepatocellular carcinoma (SHC) is a rare malignant with poor prognosis. In this study, we aimed to evaluate the clinical and pathological features of SHC and establish a nomogram that can predict long-term outcomes of the disease.
    Methods: We retrospectively analyzed 63 patients who were diagnosed with SHC between October 2007 and November 2016 and used immunohistochemistry (IHC) to assessed various markers in liver samples. The clinical data and the histological and pathological findings were collected and used to build a nomogram to predict survival.
    Results: The median overall survival (OS) and the recurrence-free survival (RFS) in SHC were 23.2 and 8.4 months, respectively. High expression levels of tyrosine-protein kinase Met (17/63, 27.0%) were associated with poorer RFS (P=0.040). A panel of markers, consisting heat-shock protein 70 (HSP70), glutamine synthetase (GS), and glypican-3 (GPC3), merged as an independent risk factor for treatment outcomes. The nomogram, which including this panel of markers, predicted OS times with a concordance-index (C-index) score of 0.758 (95% CI: 0.672-0.843) in the training set and 0.832 (95% CI: 0.712-0.952) in the validation set. The use of the nomogram showed marked improvements in the prediction of patient outcomes compared with conventional staging systems (P<0.05).
    Conclusions: Diagnosis of SHC is rare and has a relatively poor prognosis. A panel of markers HSP70, GS and GPC3 served as an independent prognostic factor for SHC.
    Keywords:  Sarcomatoid hepatocellular carcinoma (SHC); glutamine synthetase (GS); glypican-3 (GPC3); heat-shock protein 70 (HSP70); nomogram
    DOI:  https://doi.org/10.21037/atm-21-4322
  20. FASEB J. 2022 May;36 Suppl 1
    Inhibition of Anaplerosis Prevented Mitochondrial Dysfunction and Vascular Remodeling in Pulmonary Hypertension.
    Mathews Valuparampil Varghese, Joel James, Maki Niihori, Olga Rafikova, Ruslan Rafikov.
       INTRODUCTION: Pulmonary hypertension (PH) is a deadly disease of the lung vasculature. Recent studies reported mitochondrial dysfunction as a significant contributor to PH pathobiology, the prominent type of dysfunction is still unclear. Importantly, partial mitochondrial functioning is necessary to provide the metabolic intermediates for the proliferative growth of vascular cells in PH. Recently, we reported that in PH, the mitochondrial anabolic branch of metabolism - anaplerosis plays a critical role in the upregulation of the tricarboxylic acid cycle in pulmonary vascular cells with mitochondrial dysfunction.
    HYPOTHESIS: We hypothesize that the inhibition of both anaplerosis targets - pyruvate carboxylase (PC) and glutaminolysis - glutamate dehydrogenase 1 (GLUD1) in the early stages of PH could effectively attenuate mitochondrial dysfunction and vascular remodeling.
    METHODS: PH was induced in female Sprague Dawley rats by subcutaneous injection of sugen (50 mg/kg)/hypoxia (10% O2 ). The treatment groups received sugen/hypoxia (Su/Hx) and two-weeks intraperitoneal injection of inhibitors (PC inhibitor, phenylacetic acid (PAA), 20 mg/kg/every other day and R162, an inhibitor of GLUD1 (30mg/kg/daily).
    RESULTS: Hemodynamic analysis of five weeks of Su/Hx rats showed a progressive PH phenotype with increased right ventricular (RV) systolic pressure (111.08 ± 6.87 mmHg). Inhibiting anaplerosis at early stages of PH (2 weeks Su/Hx), decreased the RV hypertrophy (0.5 ± 0.02 to 0.42 ± 0.02, p<0.05), RV systolic pressure (71.88 ± 3.59 mmHg to 54.14 ± 2.48 mmHg, p<0.05), and Max dP/dt (3863.89 ± 180.27 mmHg/s to 2890.63 ± 154.52 mmHg/s, p<0.01). Su/Hx group showed an increased glycolytic flux with hexokinase-I upregulation (p<0.05), leading to an upregulation of anaplerosis. This was followed by the impairment in mitochondrial function with a reduction of pyruvate dehydrogenase (PDH) expression (p<0.001) and activation of mitochondrial glycerol-3-phosphate-dehydrogenase (GPD2) (p<0.001), an important mediator of the glycerophosphate shuttle. The increased glycolysis also fluxed into the pentose phosphate pathway (PPP) through myo-inositol oxygenase (MIOX) (p<0.001), a novel source of reactive oxygen species (ROS) generation in PH. These metabolic alterations lead to the upregulation of proliferative signaling pathways Akt (p<0.01), STAT3 (p<0.001), and P38 (p<0.01). Importantly, the inhibition of the anaplerotic pathways by combination (PAA+R162) treatment in the Su/Hx PH model significantly resolved the activation of PPP, restored mitochondrial metabolism, and prevented the proliferative signaling leading to lung vascular remodeling.
    CONCLUSION: The results suggest that inhibition of the anaplerotic pathway effectively attenuated mitochondrial dysfunction and vascular remodeling in Su/HX animals. Therefore, our findings indicate that simultaneous targeting of both PC and glutamine-mediated anaplerosis is a promising therapeutic target for the resolution of vascular remodeling in PH.
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R4126
  21. Trends Endocrinol Metab. 2022 May 06. pii: S1043-2760(22)00063-7. [Epub ahead of print]
    Metabolic oscillations during cell-cycle progression.
    Philippe Icard, Luca Simula.
      We discuss how metabolism changes during different phases of the cell cycle to sustain biosynthesis and replication in normal and cancer cells. We also highlight how several master regulators of cell cycle, such as cyclin-cyclin-dependent kinases (cyc-CDK complexes) and E3 proteasome ligases, modulate key metabolic enzymes to support cell-cycle progression.
    Keywords:  Warburg effect; cancer; cell cycle; cell metabolism
    DOI:  https://doi.org/10.1016/j.tem.2022.04.006
  22. FASEB J. 2022 May;36 Suppl 1
    Investigating the therapeutic efficacy of a novel mTORC1 inhibitor, RMC-6272, on liver tumors with b-catenin activation.
    Yekaterina Krutsenko, Junyan Tao, Mallika Singh, Satdarshan P Monga.
      Hepatocellular cancers (HCC) are a challenge to treat and lack precision-based therapies. Gain-of-function (GOF) CTNNB1 mutations are evident in around 25-35% of all HCCs. Co-expression of mutant CTNNB1 (S45Y) along with proto-oncogene Met or constitutively active Nrf2, recapitulates 11% and 10% of clinical HCC, respectively. GOF CTNNB1 mutations are also observed in >90% of hepatoblastomas (HBs). Co-expression of active β-catenin and Yap in mice leads to the development of HB, representing 80% of all cases. Aberrant activation of the mTOR complex 1 (mTORC1) is observed in both HCC and HB models. In HCC, mutant- β-catenin causes glutamine synthetase-dependent increase in glutamine, leading to increased S2448-pmTOR, indicative of mTORC1 activation. In Yap/Ctnnb1 model, mTORC1 activation occurs due to Yap-regulated increase in glutamine transporter. Here we examine the therapeutic effects of a novel mTORC1 inhibitor RMC-6272 on the progression of β-catenin-driven HCCs and HB. RMC-6272 belongs to a class of selective mTORC1 inhibitors, termed 'bi-steric', which comprise a rapamycin-like core moiety covalently linked to an mTOR active-site inhibitor.
    METHODS: Hydrodynamic tail-vein injection (HDTVI) of S127A-YAP1 and ΔN90-CTNNB1 plasmids, together with SB transposase, was used to induce HB development in FVB mice. HCC was induced by co-expression of S45YCTNNB1 with either Met or G31A-NFE2L2. Weekly IP administration of RMC-6272 (Revolution Medicines, 10 mg/kg) was started at 1 week post HDTVI in HB, at 3 weeks in Met-β-catenin, and 5 weeks in Nrf2-β-catenin models. Animals were euthanized after 7 and 11 weeks of treatment for HB; at 2.5 and 5 weeks for Met-β-catenin HCC; and 5 weeks for Nrf2- β-catenin HCC. Liver weight to body weight ratio (LW/BW) was used to address tumor burden. Durability of the RMC-6272-elicited response was studied in Yap/β-catenin and in Nrf2/β-catenin models by first administering the drug as described above, and then switching to the control treatment for 3 additional weeks, prior to sacrificing them 15 and 13 weeks, respectively, after HDTVI.
    RESULTS: Treatment with RMC-6272 significantly reduced tumor burden in all 3 models. Although both early- and late-end point groups showed some malignant growth, the size and quantity of tumors was diminished by the treatment. The tumor inhibitory effect of RMC-6272 was more pronounced at late time points by both significantly reduced LW/BW as well as by histology. Moreover, tumor suppressive effects were sustained in both a HB and in a Nrf2-β-catenin-driven HCC, as evident by the significantly reduced LW/BW, even if the treatment had been terminated 3 weeks prior to analysis.
    CONCLUSIONS: Our study demonstrates that RMC-6272, a novel bi-steric mTORC1 inhibitor, had a potent multifactorial effect on diminishing HB and HCC growth in relevant murine models. These observations further solidify the potential use of mTORC1 inhibitors as therapeutic agents for CTNNB1-mutated HCCs and in most HB cases. The bi-steric mTORC1 inhibitor RMC-5552 is the first clinical candidate of this class and clinical testing is ongoing (NCT04774952).
    DOI:  https://doi.org/10.1096/fasebj.2022.36.S1.R4865
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