bims-glucam 2021-10-03 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021‒10‒03
twenty-one papers selected by
Sreeparna Banerjee
Middle East Technical University

Glutamine Modulates Expression and Function of Glucose 6-Phosphate Dehydrogenase via NRF2 in Colon Cancer Cells.
Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric Cancer.
Can the Mitochondrial Metabolic Theory Explain Better the Origin and Management of Cancer than Can the Somatic Mutation Theory?
SREBP1-Induced Glutamine Synthetase Triggers a Feedforward Loop to Upregulate SREBP1 through Sp1 O-GlcNAcylation and Augments Lipid Droplet Formation in Cancer Cells.
Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis.
Viruses and Metabolism: The Effects of Viral Infections and Viral Insulins on Host Metabolism.
HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells.
Metabolomics analysis of the 3D L-02 cell cultures revealing the key role of metabolism of amino acids in ameliorating hepatotoxicity of perfluorooctanoic acid.
Inhibition of Metabolism as a Therapeutic Option for Tamoxifen-Resistant Breast Cancer Cells.
Foxo3a tempers excessive glutaminolysis in activated T cells to prevent fatal gut inflammation in the murine IL-10-/- model of colitis.
Salubrinal Enhances Cancer Cell Death during Glucose Deprivation through the Upregulation of xCT and Mitochondrial Oxidative Stress.
Glucose and Amino Acid Metabolic Dependencies Linked to Stemness and Metastasis in Different Aggressive Cancer Types.
The multifaceted roles of mitochondria at the crossroads of cell life and death in cancer.
USP15 antagonizes CRL4CRBN-mediated ubiquitylation of glutamine synthetase and neosubstrates.
Metabolic Reprogramming and Immune Evasion in Nasopharyngeal Carcinoma.
Clinical Targeting of Altered Metabolism in High-Grade Glioma.
Dietary Supplement Enriched in Antioxidants and Omega-3 Promotes Glutamine Synthesis in Müller Cells: A Key Process against Oxidative Stress in Retina.
Robust metabolic transcriptional components in 34,494 patient-derived cancer-related samples and cell lines.
NRF2 Mediates Therapeutic Resistance to Chemoradiation in Colorectal Cancer through a Metabolic Switch.
Identifying metabolic alterations in newly diagnosed small cell lung cancer patients.
Cancer Signaling Drives Cancer Metabolism: AKT and the Warburg Effect.

Antioxidants (Basel). 2021 Aug 25. pii: 1349. [Epub ahead of print]10(9):

Glutamine Modulates Expression and Function of Glucose 6-Phosphate Dehydrogenase via NRF2 in Colon Cancer Cells.

Ibrahim H Polat, Míriam Tarrado-Castellarnau, Adrian Benito, Claudia Hernandez-Carro, Josep Centelles, Silvia Marin, Marta Cascante.

  Nucleotide pools need to be constantly replenished in cancer cells to support cell proliferation. The synthesis of nucleotides requires glutamine and 5-phosphoribosyl-1-pyrophosphate produced from ribose-5-phosphate via the oxidative branch of the pentose phosphate pathway (ox-PPP). Both PPP and glutamine also play a key role in maintaining the redox status of cancer cells. Enhanced glutamine metabolism and increased glucose 6-phosphate dehydrogenase (G6PD) expression have been related to a malignant phenotype in tumors. However, the association between G6PD overexpression and glutamine consumption in cancer cell proliferation is still incompletely understood. In this study, we demonstrated that both inhibition of G6PD and glutamine deprivation decrease the proliferation of colon cancer cells and induce cell cycle arrest and apoptosis. Moreover, we unveiled that glutamine deprivation induce an increase of G6PD expression that is mediated through the activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2). This crosstalk between G6PD and glutamine points out the potential of combined therapies targeting oxidative PPP enzymes and glutamine catabolism to combat colon cancer.

Keywords:  cancer cell metabolism; colon cancer; glucose-6-phosphate dehydrogenase; oxidative stress; pentose phosphate pathway

DOI:  https://doi.org/10.3390/antiox10091349
Integr Cancer Ther. 2021 Jan-Dec;20:20 15347354211045349

Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric Cancer.

Huanrong Ma, Jingjing Wu, Minyu Zhou, Jianhua Wu, Zhenzhen Wu, Li Lin, Na Huang, Wangjun Liao, Li Sun.

  Treatment for advanced gastric cancer is challenging. Epidermal growth factor receptor (EGFR) contributes to the proliferation and development of gastric cancer (GC), and its overexpression is associated with unfavorable prognosis in GC. Cetuximab, a monoclonal antibody targeting EGFR, failed to improve the overall survival of gastric cancer patients indicated in phase III randomized trials. Glutamine is a vital nutrient for tumor growth and its metabolism contributes to therapeutic resistance, making glutamine uptake an attractive target for cancer treatment. The aim of the present study was to investigate whether intervention of glutamine uptake could improve the effect of cetuximab on GC. The results of MTT assay showed that by glutamine deprivation or inhibition of glutamine uptake, the viability of gastric carcinoma cells was inhibited more severely than that of human immortal gastric mucosa epithelial cells (GES-1). The expression of the key glutamine transporter alanine-serine-cysteine (ASC) transporter 2 (ASCT2; SLC1A5) was significantly higher in gastric carcinoma tissues and various gastric carcinoma cell lines than in normal gastric tissues and cells, as shown by immunohistochemistry and western blotting, while silencing ASCT2 significantly inhibited the viability and proliferation of gastric carcinoma cells. Consistent with previous studies, it was shown herein by MTT and EdU assays that cetuximab had a weak inhibitory effect on the cell viability of gastric carcinoma cells. However, inhibiting glutamine uptake by blockade of ASCT2 with l-γ-glutamyl-p-nitroanilide (GPNA) significantly enhanced the inhibitory effect of cetuximab on suppressing the proliferation of gastric cancer both in vitro and in vivo. Moreover, combining cetuximab and GPNA induced cell apoptosis considerably in gastric carcinoma cells, as shown by flow cytometry, and had a higher depressing effect on gastric cancer proliferation both in vitro and in vivo, as compared to either treatment alone. The present study suggested that inhibition of glutamine uptake may be a promising strategy for improving the inhibitory efficacy of cetuximab on advanced gastric cancer.

Keywords:  ASCT2; EGFR; cetuximab; gastric cancer; glutamine uptake

DOI:  https://doi.org/10.1177/15347354211045349
Metabolites. 2021 Aug 25. pii: 572. [Epub ahead of print]11(9):

Can the Mitochondrial Metabolic Theory Explain Better the Origin and Management of Cancer than Can the Somatic Mutation Theory?

Thomas N Seyfried, Christos Chinopoulos.

  A theory that can best explain the facts of a phenomenon is more likely to advance knowledge than a theory that is less able to explain the facts. Cancer is generally considered a genetic disease based on the somatic mutation theory (SMT) where mutations in proto-oncogenes and tumor suppressor genes cause dysregulated cell growth. Evidence is reviewed showing that the mitochondrial metabolic theory (MMT) can better account for the hallmarks of cancer than can the SMT. Proliferating cancer cells cannot survive or grow without carbons and nitrogen for the synthesis of metabolites and ATP (Adenosine Triphosphate). Glucose carbons are essential for metabolite synthesis through the glycolysis and pentose phosphate pathways while glutamine nitrogen and carbons are essential for the synthesis of nitrogen-containing metabolites and ATP through the glutaminolysis pathway. Glutamine-dependent mitochondrial substrate level phosphorylation becomes essential for ATP synthesis in cancer cells that over-express the glycolytic pyruvate kinase M2 isoform (PKM2), that have deficient OxPhos, and that can grow in either hypoxia (0.1% oxygen) or in cyanide. The simultaneous targeting of glucose and glutamine, while elevating levels of non-fermentable ketone bodies, offers a simple and parsimonious therapeutic strategy for managing most cancers.

Keywords:  IDH1; chimpanzees; evolution; fermentation; glutaminolysis; glycolysis; ketogenic metabolic therapy; metastasis; mitochondrial substrate level phosphorylation; mutations; oncogenes; respiration

DOI:  https://doi.org/10.3390/metabo11090572
Int J Mol Sci. 2021 Sep 10. pii: 9814. [Epub ahead of print]22(18):

SREBP1-Induced Glutamine Synthetase Triggers a Feedforward Loop to Upregulate SREBP1 through Sp1 O-GlcNAcylation and Augments Lipid Droplet Formation in Cancer Cells.

Jin-Wei Jhu, Jia-Bao Yan, Zou-Han Lin, Shih-Chieh Lin, I-Chen Peng.

  Glutamine and lipids are two important components of proliferating cancer cells. Studies have demonstrated that glutamine synthetase (GS) boosts glutamine-dependent anabolic processes for nucleotide and protein synthesis, but the role of GS in regulating lipogenesis remains unclear. This study identified that insulin and glutamine deprivation activated the lipogenic transcription factor sterol regulatory element-binding protein 1 (SREBP1) that bound to the GS promoter and increased its transcription. Notably, GS enhanced the O-linked N-acetylglucosaminylation (O-GlcNAcylation) of the specificity protein 1 (Sp1) that induced SREBP1/acetyl-CoA carboxylase 1 (ACC1) expression resulting in lipid droplet (LD) accumulation upon insulin treatment. Moreover, glutamine deprivation induced LD formation through GS-mediated O-GlcNAc-Sp1/SREBP1/ACC1 signaling and supported cell survival. These findings demonstrate that insulin and glutamine deprivation induces SREBP1 that transcriptionally activates GS, resulting in Sp1 O-GlcNAcylation. Subsequently, O-GlcNAc-Sp1 transcriptionally upregulates the expression of SREBP1, resulting in a feedforward loop that increases lipogenesis and LD formation in liver and breast cancer cells.

Keywords:  O-GlcNAcylation; cancer; glutamine synthetase; lipid droplet; sterol regulatory element-binding protein 1

DOI:  https://doi.org/10.3390/ijms22189814
Genes (Basel). 2021 Aug 25. pii: 1305. [Epub ahead of print]12(9):

Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis.

Jingwen Zou, Kunpeng Du, Shaohua Li, Lianghe Lu, Jie Mei, Wenping Lin, Min Deng, Wei Wei, Rongping Guo.

  BACKGROUND: In recent years, metabolic reprogramming has been identified as a hallmark of cancer. Accumulating evidence suggests that glutamine metabolism plays a crucial role in oncogenesis and the tumor microenvironment. In this study, we aimed to perform a systematic and comprehensive analysis of six key metabolic node genes involved in the dynamic regulation of glutamine metabolism (referred to as GLNM regulators) across 33 types of cancer.METHODS: We analyzed the gene expression, epigenetic regulation, and genomic alterations of six key GLNM regulators, including SLC1A5, SLC7A5, SLC3A2, SLC7A11, GLS, and GLS2, in pan-cancer using several open-source platforms and databases. Additionally, we investigated the impacts of these gene expression changes on clinical outcomes, drug sensitivity, and the tumor microenvironment. We also attempted to investigate the upstream microRNA-mRNA molecular networks and the downstream signaling pathways involved in order to uncover the potential molecular mechanisms behind metabolic reprogramming.
RESULTS: We found that the expression levels of GLNM regulators varied across cancer types and were related to several genomic and immunological characteristics. While the immune scores were generally lower in the tumors with higher gene expression, the types of immune cell infiltration showed significantly different correlations among cancer types, dividing them into two clusters. Furthermore, we showed that elevated GLNM regulators expression was associated with poor overall survival in the majority of cancer types. Lastly, the expression of GLNM regulators was significantly associated with PD-L1 expression and drug sensitivity.
CONCLUSIONS: The elevated expression of GLNM regulators was associated with poorer cancer prognoses and a cold tumor microenvironment, providing novel insights into cancer treatment and possibly offering alternative options for the treatment of clinically refractory cancers.

Keywords:  PD-L1; glutamine; immune; metabolism; multi-omics; pan-cancer

DOI:  https://doi.org/10.3390/genes12091305
Annu Rev Virol. 2021 Sep 29. 8(1): 373-391

Viruses and Metabolism: The Effects of Viral Infections and Viral Insulins on Host Metabolism.

Khyati Girdhar, Amaya Powis, Amol Raisingani, Martina Chrudinová, Ruixu Huang, Tu Tran, Kaan Sevgi, Yusuf Dogus Dogru, Emrah Altindis.

  Over the past decades, there have been tremendous efforts to understand the cross-talk between viruses and host metabolism. Several studies have elucidated the mechanisms through which viral infections manipulate metabolic pathways including glucose, fatty acid, protein, and nucleotide metabolism. These pathways are evolutionarily conserved across the tree of life and extremely important for the host's nutrient utilization and energy production. In this review, we focus on host glucose, glutamine, and fatty acid metabolism and highlight the pathways manipulated by the different classes of viruses to increase their replication. We also explore a new system of viral hormones in which viruses mimic host hormones to manipulate the host endocrine system. We discuss viral insulin/IGF-1-like peptides and their potential effects on host metabolism. Together, these pathogenesis mechanisms targeting cellular signaling pathways create a multidimensional network of interactions between host and viral proteins. Defining and better understanding these mechanisms will help us to develop new therapeutic tools to prevent and treat viral infections.

Keywords:  glutaminolysis; glycolysis; lipid metabolism; metabolism; viral insulins; viruses

DOI:  https://doi.org/10.1146/annurev-virology-091919-102416
Cells. 2021 Sep 09. pii: 2371. [Epub ahead of print]10(9):

HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells.

Shen-Han Lee, Monika Golinska, John R Griffiths.

  In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1β rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1β for activation. However, HIF-1β is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms.

Keywords:  2-hydroxyglutarate; AMP-activated protein kinase (AMPK); Myc; cancer metabolism; creatine metabolism; glutamine metabolism; glycolysis; hypoxia; hypoxia-inducible factor-1 (HIF-1); lipid metabolism; phosphatidylinositol 3-kinase (PI3K)

DOI:  https://doi.org/10.3390/cells10092371
Sci Total Environ. 2021 Sep 20. pii: S0048-9697(21)05515-7. [Epub ahead of print]806(Pt 1): 150438

Metabolomics analysis of the 3D L-02 cell cultures revealing the key role of metabolism of amino acids in ameliorating hepatotoxicity of perfluorooctanoic acid.

Ruijia Zhang, Wenhua Lu, Yao Yao, Lanyin Tu, Tiantian Yu, Tiangang Luan, Baowei Chen.

  To simulate the real cell status and morphology in the living systems is substantial for using cell models to address the detrimental effects of toxic contaminants. In this study, the comparative profiles of metabolites in three-dimensional (3D) human normal liver (L-02) cell spheroids with perfluorooctanoic acid (PFOA) treatment were analyzed using a metabolomic approach. The uniform 3D cell spheroids were well formed in 3 days (e.g., sphericity index >0.9) and stably maintained over the subsequent 11 days. The cytotoxicity of PFOA to the 3D L-02 cell spheroids was highly dependent on both exposure concentration and duration. Comparative analysis of metabolomes showed that the number of differential metabolites in the 3D cell spheroids treated with 300 μM PFOA for 10 days (n = 59) was greater than those with a 4-day exposure to 300 μM PFOA (n = 17). Six metabolic pathways related to amino acids metabolism were only found in the 3D cell spheroids with a 10-day treatment of 300 μM PFOA, which could not be found in the 2D monolayer cells and those 3D cell spheroids with a 4-day exposure. The suppression of PFOA on glutamine metabolism substantially decreased glutathione (GSH) production and accordingly increased the level of reactive oxygen species in the 3D cell spheroids. On the contrary, the supplementation of glutamine increased GSH production and the viability of cell spheroids, indicating that glutamine metabolism played a critical role in the chronic toxic effects of PFOA. Our study strongly suggested that comprehensive toxicological methodologies based on the 3D cell models could currently be robust and suitable for addressing the chronic adverse effects of toxic contaminants.

Keywords:  3D cell spheroids; Amino acids; Metabolomics; Perfluorooctanoic acid

DOI:  https://doi.org/10.1016/j.scitotenv.2021.150438
Cells. 2021 Sep 12. pii: 2398. [Epub ahead of print]10(9):

Inhibition of Metabolism as a Therapeutic Option for Tamoxifen-Resistant Breast Cancer Cells.

Friederike Steifensand, Julia Gallwas, Gerd Bauerschmitz, Carsten Gründker.

  Cancer cells have an increased need for glucose and, despite aerobic conditions, obtain their energy through aerobic oxidation and lactate fermentation, instead of aerobic oxidation alone. Glutamine is an essential amino acid in the human body. Glutaminolysis and glycolysis are crucial for cancer cell survival. In the therapy of estrogen receptor α (ERα)-positive breast cancer (BC), the focus lies on hormone sensitivity targeting therapy with selective estrogen receptor modulators (SERMs) such as 4-hydroxytamoxifen (4-OHT), although this therapy is partially limited by the development of resistance. Therefore, further targets for therapy improvement of ERα-positive BC with secondary 4-OHT resistance are needed. Hence, increased glucose requirement and upregulated glutaminolysis in BC cells could be used. We have established sublines of ERα-positive MCF7 and T47D BC cells, which were developed to be resistant to 4-OHT. Further, glycolysis inhibitor 2-Deoxy-D-Glucose (2-DG) and glutaminase inhibitor CB-839 were analyzed. Co-treatments using 4-OHT and CB-839, 2-DG and CB-839, or 4-OHT, 2-DG and CB-839, respectively, showed significantly stronger inhibitory effects on viability compared to single treatments. It could be shown that tamoxifen-resistant BC cell lines, compared to the non-resistant cell lines, exhibited a stronger reducing effect on cell viability under co-treatments. In addition, the tamoxifen-resistant BC cell lines showed increased expression of proto-oncogene c-Myc compared to the parental cell lines. This could be reduced depending on the treatment. Suppression of c-Myc expression using specific siRNA completely abolished resistance to 4OH-tamoxifen. In summary, our data suggest that combined treatments affecting the metabolism of BC are suitable depending on the cellularity and resistance status. In addition, the anti-metabolic treatments affected the expression of the proto-oncogene c-Myc, a key player in the regulation of cancer cell metabolism.

Keywords:  breast cancer; estrogen receptor α; glutaminolysis; glycolysis; tamoxifen resistance

DOI:  https://doi.org/10.3390/cells10092398
Cell Death Differ. 2021 Sep 29.

Foxo3a tempers excessive glutaminolysis in activated T cells to prevent fatal gut inflammation in the murine IL-10-/- model of colitis.

Stephanie Hajjar, Nayanan Nathan, Julie Joseph, Walid Mottawea, Ardeshir Ariana, Sergey Pyatibrat, Mary-Ellen Harper, Tommy Alain, Alexandre Blais, Ryan C Russell, Subash Sad.

Mutations in susceptibility alleles correlate with gut-inflammatory diseases, such as Crohn's disease; however, this does not often impact the disease progression indicating the existence of compensatory genes. We show that a reduction in Foxo3a expression in IL-10-deficient mice results in a spontaneous and aggressive Crohn's- like disease with 100% penetrance, which is rescued by deletion of myeloid cells, T cells and inhibition of mTORC1. In Foxo3a-/- IL-10-/- mice, there is poor cell death of myeloid cells in the gut, leading to increased accumulation of myeloid and T cells in the gut. Myeloid cells express high levels of inflammatory cytokines, and regulatory T cells are dysfunctional despite increased abundance. Foxo3a signaling represses the transcription of glutaminase (GLS/GLS2) to prevent over-consumption of glutamine by activated T cells and its conversion to glutamate that contributes to the TCA cycle and mTORC1 activation. Finally, we show that Foxo3a restricts the abundance of colitogenic microbiota in IL-10-deficient mice. Thus, by suppressing glutaminolysis in activated T cells Foxo3a mediates a critical checkpoint that prevents the development of fulminant gut inflammatory disease.

DOI: https://doi.org/10.1038/s41418-021-00876-y
Biomedicines. 2021 Aug 28. pii: 1101. [Epub ahead of print]9(9):

Salubrinal Enhances Cancer Cell Death during Glucose Deprivation through the Upregulation of xCT and Mitochondrial Oxidative Stress.

Mei-Chun Chen, Li-Lin Hsu, Sheng-Fan Wang, Yi-Ling Pan, Jeng-Fan Lo, Tien-Shun Yeh, Ling-Ming Tseng, Hsin-Chen Lee.

  Cancer cells have the metabolic flexibility to adapt to heterogeneous tumor microenvironments. The integrated stress response (ISR) regulates the cellular adaptation response during nutrient stress. However, the issue of how the ISR regulates metabolic flexibility is still poorly understood. In this study, we activated the ISR using salubrinal in cancer cells and found that salubrinal repressed cell growth, colony formation, and migration but did not induce cell death in a glucose-containing condition. Under a glucose-deprivation condition, salubrinal induced cell death and increased the levels of mitochondrial reactive oxygen species (ROS). We found that these effects of salubrinal and glucose deprivation were associated with the upregulation of xCT (SLC7A11), which functions as an antiporter of cystine and glutamate and maintains the level of glutathione to maintain redox homeostasis. The upregulation of xCT did not protect cells from oxidative stress-mediated cell death but promoted it during glucose deprivation. In addition, the supplementation of ROS scavenger N-acetylcysteine and the maintenance of intracellular levels of amino acids via sulfasalazine (xCT inhibitor) or dimethyl-α-ketoglutarate decreased the levels of mitochondrial ROS and protected cells from death. Our results suggested that salubrinal enhances cancer cell death during glucose deprivation through the upregulation of xCT and mitochondrial oxidative stress.

Keywords:  integrated stress response; oxidative stress; salubrinal; xCT

DOI:  https://doi.org/10.3390/biomedicines9091101
Front Pharmacol. 2021 ;12 723798

Glucose and Amino Acid Metabolic Dependencies Linked to Stemness and Metastasis in Different Aggressive Cancer Types.

Andrea Chisari, Irene Golán, Sabrina Campisano, Caroline Gélabert, Aristidis Moustakas, Patricia Sancho, Laia Caja.

  Malignant cells are commonly characterised by being capable of invading tissue, growing self-sufficiently and uncontrollably, being insensitive to apoptosis induction and controlling their environment, for example inducing angiogenesis. Amongst them, a subpopulation of cancer cells, called cancer stem cells (CSCs) shows sustained replicative potential, tumor-initiating properties and chemoresistance. These characteristics make CSCs responsible for therapy resistance, tumor relapse and growth in distant organs, causing metastatic dissemination. For these reasons, eliminating CSCs is necessary in order to achieve long-term survival of cancer patients. New insights in cancer metabolism have revealed that cellular metabolism in tumors is highly heterogeneous and that CSCs show specific metabolic traits supporting their unique functionality. Indeed, CSCs adapt differently to the deprivation of specific nutrients that represent potentially targetable vulnerabilities. This review focuses on three of the most aggressive tumor types: pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC) and glioblastoma (GBM). The aim is to prove whether CSCs from different tumour types share common metabolic requirements and responses to nutrient starvation, by outlining the diverse roles of glucose and amino acids within tumour cells and in the tumour microenvironment, as well as the consequences of their deprivation. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, glucose and amino acid derivatives contribute to immune responses linked to tumourigenesis and metastasis. Furthermore, potential metabolic liabilities are identified and discussed as targets for therapeutic intervention.

Keywords:  GBM-glioblastoma multiforme; HCC-hepatocellular carcinoma; PDAC-pancreatic ductal adenocarcinoma; amino acid; cancer stem cell (CSC); glucose; therapy

DOI:  https://doi.org/10.3389/fphar.2021.723798
Free Radic Biol Med. 2021 Sep 28. pii: S0891-5849(21)00744-9. [Epub ahead of print]

The multifaceted roles of mitochondria at the crossroads of cell life and death in cancer.

Fabrizio Fontana, Patrizia Limonta.

  Mitochondria are the cytoplasmic organelles mostly known as the "electric engine" of the cells; however, they also play pivotal roles in different biological processes, such as cell growth/apoptosis, Ca2+ and redox homeostasis, and cell stemness. In cancer cells, mitochondria undergo peculiar functional and structural dynamics involved in the survival/death fate of the cell. Cancer cells use glycolysis to support macromolecular biosynthesis and energy production ("Warburg effect"); however, mitochondrial OXPHOS has been shown to be still active during carcinogenesis and even exacerbated in drug-resistant and stem cancer cells. This metabolic rewiring is associated with mutations in genes encoding mitochondrial metabolic enzymes ("oncometabolites"), alterations of ROS production and redox biology, and a fine-tuned balance between anti-/proapoptotic proteins. In cancer cells, mitochondria also experience dynamic alterations from the structural point of view undergoing coordinated cycles of biogenesis, fusion/fission and mitophagy, and physically communicating with the endoplasmic reticulum (ER), through the Ca2+ flux, at the MAM (mitochondria-associated membranes) levels. This review addresses the peculiar mitochondrial metabolic and structural dynamics occurring in cancer cells and their role in coordinating the balance between cell survival and death. The role of mitochondrial dynamics as effective biomarkers of tumor progression and promising targets for anticancer strategies is also discussed.

Keywords:  Cancer; MAMs; Metabolic rewiring; Mitochondria; OXPHOS; ROS; Structural dynamics

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.09.024
Proc Natl Acad Sci U S A. 2021 Oct 05. pii: e2111391118. [Epub ahead of print]118(40):

USP15 antagonizes CRL4CRBN-mediated ubiquitylation of glutamine synthetase and neosubstrates.

Thang Van Nguyen.

  Targeted protein degradation by the ubiquitin-proteasome system represents a new strategy to destroy pathogenic proteins in human diseases, including cancer and neurodegenerative diseases. The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide have revolutionized the treatment of patients with multiple myeloma (MM) and other hematologic malignancies, but almost all patients eventually develop resistance to IMiDs. CRBN, a substrate receptor of CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase, is a direct target for thalidomide teratogenicity and antitumor activity of IMiDs (now known as Cereblon E3 ligase modulators: CELMoDs). Despite recent advances in developing potent CELMoDs and CRBN-based proteolysis-targeting chimeras (PROTACs), many questions apart from clinical efficacy remain unanswered. CRBN is required for the action of IMiDs, but its protein expression levels do not correlate with intrinsic resistance to IMiDs in MM cells, suggesting other factors involved in regulating resistance to IMiDs. Our recent work revealed that the CRL4CRBN-p97 pathway is required for degradation of natural substrate glutamine synthetase (GS) and neosubstrates. Here, I show that USP15 is a key regulator of the CRL4CRBN-p97 pathway to control stability of GS and neosubstrates IKZF1, IKZF3, CK1-α, RNF166, GSPT1, and BRD4, all of which are crucial drug targets in different types of cancer. USP15 antagonizes ubiquitylation of CRL4CRBN target proteins, thereby preventing their degradation. Notably, USP15 is highly expressed in IMiD-resistant cells, and depletion of USP15 sensitizes these cells to lenalidomide. Inhibition of USP15 represents a valuable therapeutic opportunity to potentiate CELMoD and CRBN-based PROTAC therapies for the treatment of cancer.

Keywords:  CRBN; IMiDs; PROTACs; USP15; ubiquitin

DOI:  https://doi.org/10.1073/pnas.2111391118
Front Immunol. 2021 ;12 680955

Metabolic Reprogramming and Immune Evasion in Nasopharyngeal Carcinoma.

Huimei Huang, Shisheng Li, Qinglai Tang, Gangcai Zhu.

  Nasopharyngeal carcinoma (NPC) is a malignant tumor of the nasopharynx mainly characterized by geographic distribution and EBV infection. Metabolic reprogramming, one of the cancer hallmarks, has been frequently reported in NPCs to adapt to internal energy demands and external environmental pressures. Inevitably, the metabolic reprogramming within the tumor cell will lead to a decreased pH value and diverse nutritional supplements in the tumor-infiltrating micro-environment incorporating immune cells, fibroblasts, and endothelial cells. Accumulated evidence indicates that metabolic reprogramming derived from NPC cells may facilitate cancer progression and immunosuppression by cell-cell communications with their surrounding immune cells. This review presents the dysregulated metabolism processes, including glucose, fatty acid, amino acid, nucleotide metabolism, and their mutual interactions in NPC. Moreover, the potential connections between reprogrammed metabolism, tumor immunity, and associated therapy would be discussed in this review. Accordingly, the development of targets on the interactions between metabolic reprogramming and immune cells may provide assistances to overcome the current treatment resistance in NPC patients.

Keywords:  immune cell; immunotherapy; metabolism; nasopharyngeal carcinoma; pH

DOI:  https://doi.org/10.3389/fimmu.2021.680955
Cancer J. 2021 Sep-Oct 01;27(5):27(5): 386-394

Clinical Targeting of Altered Metabolism in High-Grade Glioma.

Andrew J Scott, Costas A Lyssiotis, Daniel R Wahl.

ABSTRACT: High-grade gliomas are among the deadliest of all cancers despite standard treatments, and new therapeutic strategies are needed to improve patient outcome. Targeting the altered metabolic state of tumors with traditional chemotherapeutic agents has a history of success, and our increased understanding of cellular metabolism in the past 2 decades has reinvigorated the concept of novel metabolic therapies in brain tumors. Here we highlight metabolic alterations in advanced gliomas and their translation into clinical trials using both novel agents and already established drugs repurposed for cancer treatment in an effort to improve outcome for these deadly diseases.

DOI: https://doi.org/10.1097/PPO.0000000000000550
Nutrients. 2021 Sep 16. pii: 3216. [Epub ahead of print]13(9):

Dietary Supplement Enriched in Antioxidants and Omega-3 Promotes Glutamine Synthesis in Müller Cells: A Key Process against Oxidative Stress in Retina.

Maryvonne Ardourel, Chloé Felgerolle, Arnaud Pâris, Niyazi Acar, Khaoula Ramchani Ben Othman, Natsuko Ueda, Rafaelle Rossignol, Audrey Bazinet, Betty Hébert, Sylvain Briault, Isabelle Ranchon-Cole, Olivier Perche.

  To prevent ocular pathologies, new generation of dietary supplements have been commercially available. They consist of nutritional supplement mixing components known to provide antioxidative properties, such as unsaturated fatty acid, resveratrol or flavonoids. However, to date, only one preclinical study has evaluated the impact of a mixture mainly composed of those components (Nutrof Total®) on the retina and demonstrated that in vivo supplementation prevents the retina from structural and functional injuries induced by light. Considering the crucial role played by the glial Müller cells in the retina, particularly to regulate the glutamate cycle to prevent damage in oxidative stress conditions, we questioned the impact of this ocular supplement on the glutamate metabolic cycle. To this end, various molecular aspects associated with the glutamate/glutamine metabolism cycle in Müller cells were investigated on primary Müller cells cultures incubated, or not, with the commercially mix supplement before being subjected, or not, to oxidative conditions. Our results demonstrated that in vitro supplementation provides guidance of the glutamate/glutamine cycle in favor of glutamine synthesis. These results suggest that glutamine synthesis is a crucial cellular process of retinal protection against oxidative damages and could be a key step in the previous in vivo beneficial results provided by the dietary supplementation.

Keywords:  Müller cells; glutamate; glutamine; nutritional supplementation; oxidative stress

DOI:  https://doi.org/10.3390/nu13093216
Cancer Metab. 2021 Sep 26. 9(1): 35

Robust metabolic transcriptional components in 34,494 patient-derived cancer-related samples and cell lines.

V C Leeuwenburgh, C G Urzúa-Traslaviña, A Bhattacharya, M T C Walvoort, M Jalving, S de Jong, R S N Fehrmann.

  BACKGROUND: Patient-derived bulk expression profiles of cancers can provide insight into the transcriptional changes that underlie reprogrammed metabolism in cancer. These profiles represent the average expression pattern of all heterogeneous tumor and non-tumor cells present in biopsies of tumor lesions. Hence, subtle transcriptional footprints of metabolic processes can be concealed by other biological processes and experimental artifacts. However, consensus independent component analyses (c-ICA) can capture statistically independent transcriptional footprints of both subtle and more pronounced metabolic processes.METHODS: We performed c-ICA with 34,494 bulk expression profiles of patient-derived tumor biopsies, non-cancer tissues, and cell lines. Gene set enrichment analysis with 608 gene sets that describe metabolic processes was performed to identify the transcriptional components enriched for metabolic processes (mTCs). The activity of these mTCs was determined in all samples to create a metabolic transcriptional landscape.
RESULTS: A set of 555 mTCs was identified of which many were robust across different datasets, platforms, and patient-derived tissues and cell lines. We demonstrate how the metabolic transcriptional landscape defined by the activity of these mTCs in samples can be used to explore the associations between the metabolic transcriptome and drug sensitivities, patient outcomes, and the composition of the immune tumor microenvironment.
CONCLUSIONS: To facilitate the use of our transcriptional metabolic landscape, we have provided access to all data via a web portal ( www.themetaboliclandscapeofcancer.com ). We believe this resource will contribute to the formulation of new hypotheses on how to metabolically engage the tumor or its (immune) microenvironment.

Keywords:  Drug sensitivity; Independent component analysis; Metabolism; Transcriptome; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40170-021-00272-7
Antioxidants (Basel). 2021 Aug 28. pii: 1380. [Epub ahead of print]10(9):

NRF2 Mediates Therapeutic Resistance to Chemoradiation in Colorectal Cancer through a Metabolic Switch.

Séan M O'Cathail, Chieh-Hsi Wu, Rachael Thomas, Maria A Hawkins, Tim S Maughan, Annabelle Lewis.

  Radiation resistance is a significant clinical problem in rectal cancer treatment, the mechanisms of which are poorly understood. NRF2 signalling is known to contribute to chemo/radioresistance in some cancers, but its role in therapeutic resistance in colorectal cancer (CRC) is unexplored. Using siRNA and CRiSPR/Cas9 isogenic CRC cell lines, we investigated the effect of the knockdown and upregulation of the NRF2 pathway on chemo-radiosensitivity. Poly (A) enriched RNA sequencing and geneset enrichment analysis (GSEA) were carried out on both sensitive and resistant cell models for mechanistic insights. Finally, a cohort of rectal patient samples was profiled to understand the clinical relevance of NRF2 signalling. Radioresistant cell lines were significantly radiosensitised by siRNA knockdown (SW1463, SER10 1.22, ANOVA p < 0.0001; HT55, SER10 1.17, ANOVA p < 0.01), but not the (already) radiosensitive HCT116. The constitutive activation of NRF2 via a CRISPR Cas9 NFE2L2 mutation, E79K, induced radioresistance in HCT116 (SER10 0.71, ANOVA, p < 0.0001). GSEA demonstrated significant opposing metabolic dependencies in NRF2 signalling, specifically, the downregulation of amino acid and protein synthesis with low levels of NRF2 and upregulation with over expression. In a clinical cohort of 127 rectal patients, using a validated mRNA signature, higher baseline NRF2 signalling was associated with incomplete responses to radiation higher final neoadjuvant rectal (NAR) score (OR 1.34, 95% C.I. 1.01-1.80, LRT p-value = 0.023), where high NAR indicates poor radiation response and poor long-term prognosis. This is the first demonstration of NRF2-mediated radiation resistance in colorectal cancer. NRF2 appears to regulate crucial metabolic pathways, which could be exploited for therapeutic interventions.

Keywords:  NRF2; metabolism; radiation; therapeutic resistance

DOI:  https://doi.org/10.3390/antiox10091380
Metabol Open. 2021 Dec;12 100127

Identifying metabolic alterations in newly diagnosed small cell lung cancer patients.

Shona Pedersen, Joachim Bavnhøj Hansen, Raluca Georgiana Maltesen, Weronika Maria Szejniuk, Trygve Andreassen, Ursula Falkmer, Søren Risom Kristensen.

  Background: Small cell lung cancer (SCLC) is a malignant disease with poor prognosis. At the time of diagnosis most patients are already in a metastatic stage. Current diagnosis is based on imaging, histopathology, and immunohistochemistry, but no blood-based biomarkers have yet proven to be clinically successful for diagnosis and screening. The precise mechanisms of SCLC are not fully understood, however, several genetic mutations, protein and metabolic aberrations have been described. We aim at identifying metabolite alterations related to SCLC and to expand our knowledge relating to this aggressive cancer.Methods: A total of 30 serum samples of patients with SCLC, collected at the time of diagnosis, and 25 samples of healthy controls were included in this study. The samples were analyzed with nuclear magnetic resonance spectroscopy. Multivariate, univariate and pathways analyses were performed.
Results: Several metabolites were identified to be altered in the pre-treatment serum samples of small-cell lung cancer patients compared to healthy individuals. Metabolites involved in tricarboxylic acid cycle (succinate: fold change (FC) = 2.4, p = 0.068), lipid metabolism (LDL triglyceride: FC = 1.3, p = 0.001; LDL-1 triglyceride: FC = 1.3, p = 0.012; LDL-2 triglyceride: FC = 1.4, p = 0.009; LDL-6 triglyceride: FC = 1.5, p < 0.001; LDL-4 cholesterol: FC = 0.5, p = 0.007; HDL-3 free cholesterol: FC = 0.7, p = 0.002; HDL-4 cholesterol FC = 0.8, p < 0.001; HDL-4 apolipoprotein-A1: FC = 0.8, p = 0.005; HDL-4 apolipoprotein-A2: FC ≥ 0.7, p ≤ 0.001), amino acids (glutamic acid: FC = 1.7, p < 0.001; glutamine: FC = 0.9, p = 0.007, leucine: FC = 0.8, p < 0.001; isoleucine: FC = 0.8, p = 0.016; valine: FC = 0.9, p = 0.032; lysine: FC = 0.8, p = 0.004; methionine: FC = 0.8, p < 0.001; tyrosine: FC = 0.7, p = 0.002; creatine: FC = 0.9, p = 0.030), and ketone body metabolism (3-hydroxybutyric acid FC = 2.5, p < 0.001; acetone FC = 1.6, p < 0.001), among other, were found deranged in SCLC.
Conclusions: This study provides novel insight into the metabolic disturbances in pre-treatment SCLC patients, expanding our molecular understanding of this malignant disease.

Keywords:  Diagnostic signatures; Metabolomics; Pathways; Serum metabolites; Small-cell lung cancer

DOI:  https://doi.org/10.1016/j.metop.2021.100127
Cancer Res. 2021 Oct 01. 81(19): 4896-4898

Cancer Signaling Drives Cancer Metabolism: AKT and the Warburg Effect.

Aaron M Hosios, Brendan D Manning.

The Warburg effect, the propensity of some cells to metabolize glucose to lactate in the presence of oxygen (also known as aerobic glycolysis), has long been observed in cancer and other contexts of cell proliferation, but only in the past two decades have significant gains been made in understanding how and why this metabolic transformation occurs. In 2004, Cancer Research published a study by Elstrom and colleagues that provided one of the first connections between a specific oncogene and aerobic glycolysis. Studying hematopoietic and glioblastoma cell lines, they demonstrated that constitutive activation of AKT promotes an increased glycolytic rate without altering proliferation or oxygen consumption in culture. They proposed that it is this effect that allows constitutive AKT activation to transform cells and found that it sensitizes cells to glucose deprivation. In the years since, mechanistic understanding of oncogenic control of metabolism, and glycolysis specifically, has deepened substantially. Current work seeks to understand the benefits and liabilities associated with glycolytic metabolism and to identify inhibitors that might be of clinical benefit to target glycolytic cancer cells.See related article by Elstrom and colleagues, Cancer Res 2004;64:3892-9.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-2647