bims-glucam 2022-01-23 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–01–23
eleven papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting glutamine metabolism network for the treatment of therapy-resistant prostate cancer.
Qici Sanling Decoction Suppresses Glutamine Consumption and Bladder Cancer Cell Growth through Inhibiting c-Myc Expression.
Circulating metabolite homeostasis achieved through mass action.
The H+ Transporter SLC4A11: Roles in Metabolism, Oxidative Stress and Mitochondrial Uncoupling.
Unveiling Metabolic Vulnerability and Plasticity of Human Osteosarcoma Stem and Differentiated Cells to Improve Cancer Therapy.
Exosome derived circTRPS1 promotes malignant phenotype and CD8+ T cell exhaustion in bladder cancer microenvironment through modulating reactive oxygen species equilibrium via GLS1 mediated glutamine metabolism alteration.
Metabolomic Analysis of Carbohydrate and Amino Acid Changes Induced by Hypoxia in Naked Mole-Rat Brain and Liver.
Interactions with stromal cells promote a more oxidized cancer cell redox state in pancreatic tumors.
Genomic alterations drive metastases formation in pancreatic ductal adenocarcinoma cancer: deciphering the role of CDKN2A and CDKN2B in mediating liver tropism.
Harnessing oxidative stress for anti-glioma therapy.
Glutamine synthetase evolutionary history revisited: tracing back beyond the Last Universal Common Ancestor.

Oncogene. 2022 Jan 20.

Targeting glutamine metabolism network for the treatment of therapy-resistant prostate cancer.

Lingfan Xu, Bing Zhao, William Butler, Huan Xu, Nan Song, Xufeng Chen, J Spencer Hauck, Xia Gao, Hong Zhang, Jeff Groth, Qing Yang, Yue Zhao, David Moon, Daniel George, Yinglu Zhou, Yiping He, Jiaoti Huang.

Advanced and aggressive prostate cancer (PCa) depends on glutamine for survival and proliferation. We have previously shown that inhibition of glutaminase 1, which catalyzes the rate-limiting step of glutamine catabolism, achieves significant therapeutic effect; however, therapy resistance is inevitable. Here we report that while the glutamine carbon is critical to PCa survival, a parallel pathway of glutamine nitrogen catabolism that actively contributes to pyrimidine assembly is equally important for PCa cells. Importantly, we demonstrate a reciprocal feedback mechanism between glutamine carbon and nitrogen pathways which leads to therapy resistance when one of the two pathways is inhibited. Combination treatment to inhibit both pathways simultaneously yields better clinical outcome for advanced PCa patients.

DOI: https://doi.org/10.1038/s41388-021-02155-z
J Oncol. 2022 ;2022 7985468

Qici Sanling Decoction Suppresses Glutamine Consumption and Bladder Cancer Cell Growth through Inhibiting c-Myc Expression.

Weihua Chen, Weifeng Wang, Jun Zhang, Guoqiang Liao, Jie Bai, Bo Yang, Mingyue Tan, Hua Gong.

Traditional Chinese medicine (TCM) is widely used as an alternative therapy for cancer treatment in China. Glutamine catabolism plays an important role in cancer development. Qici Sanling decoction (QCSL) suppresses bladder cancer growth. However, the association between QCSL and glutamine catabolism remains unknown. In this study, different doses of QCSL were applied to T24 cells, followed by the measurements of cell viability and apoptosis using CCK-8 and Annexin V/PI assay, respectively. Furthermore, glutamine consumption was detected using the glutamine assay kit. QCSL was observed to inhibit cell growth and induced cell apoptosis in a dose-dependent manner. Analysis of glutamine consumption revealed that QCSL suppressed glutamine consumption in T24 cells. Furthermore, QCSL decreased the mRNA and protein levels of c-Myc, GLS1, and SLC1A5. All these effects induced by QCSL could be alleviated by c-Myc overexpression, indicating c-Myc was involved in the protective role of QCSL in bladder cancer. In addition, QCSL was found to inhibit tumor growth in the xenograft tumor model. The similar results were obtained in tumor samples that protein levels of c-Myc, GLS1, and SLC1A5 were decreased upon treatment with QCSL. In conclusion, QCSL suppresses glutamine consumption and bladder cancer cell growth through inhibiting c-Myc expression.

DOI: https://doi.org/10.1155/2022/7985468
Nat Metab. 2022 Jan 20.

Circulating metabolite homeostasis achieved through mass action.

Xiaoxuan Li, Sheng Hui, Emily T Mirek, William O Jonsson, Tracy G Anthony, Won Dong Lee, Xianfeng Zeng, Cholsoon Jang, Joshua D Rabinowitz.

Homeostasis maintains serum metabolites within physiological ranges. For glucose, this requires insulin, which suppresses glucose production while accelerating its consumption. For other circulating metabolites, a comparable master regulator has yet to be discovered. Here we show that, in mice, many circulating metabolites are cleared via the tricarboxylic acid cycle (TCA) cycle in linear proportionality to their circulating concentration. Abundant circulating metabolites (essential amino acids, serine, alanine, citrate, 3-hydroxybutyrate) were administered intravenously in perturbative amounts and their fluxes were measured using isotope labelling. The increased circulating concentrations induced by the perturbative infusions hardly altered production fluxes while linearly enhancing consumption fluxes and TCA contributions. The same mass action relationship between concentration and consumption flux largely held across feeding, fasting and high- and low-protein diets, with amino acid homeostasis during fasting further supported by enhanced endogenous protein catabolism. Thus, despite the copious regulatory machinery in mammals, circulating metabolite homeostasis is achieved substantially through mass action-driven oxidation.

DOI: https://doi.org/10.1038/s42255-021-00517-1
Cells. 2022 Jan 07. pii: 197. [Epub ahead of print]11(2):

The H+ Transporter SLC4A11: Roles in Metabolism, Oxidative Stress and Mitochondrial Uncoupling.

Joseph A Bonanno, Raji Shyam, Moonjung Choi, Diego G Ogando.

  Solute-linked cotransporter, SLC4A11, a member of the bicarbonate transporter family, is an electrogenic H+ transporter activated by NH3 and alkaline pH. Although SLC4A11 does not transport bicarbonate, it shares many properties with other members of the SLC4 family. SLC4A11 mutations can lead to corneal endothelial dystrophy and hearing deficits that are recapitulated in SLC4A11 knock-out mice. SLC4A11, at the inner mitochondrial membrane, facilitates glutamine catabolism and suppresses the production of mitochondrial superoxide by providing ammonia-sensitive H+ uncoupling that reduces glutamine-driven mitochondrial membrane potential hyperpolarization. Mitochondrial oxidative stress in SLC4A11 KO also triggers dysfunctional autophagy and lysosomes, as well as ER stress. SLC4A11 expression is induced by oxidative stress through the transcription factor NRF2, the master regulator of antioxidant genes. Outside of the corneal endothelium, SLC4A11's function has been demonstrated in cochlear fibrocytes, salivary glands, and kidneys, but is largely unexplored overall. Increased SLC4A11 expression is a component of some "glutamine-addicted" cancers, and is possibly linked to cells and tissues that rely on glutamine catabolism.

Keywords:  MCT4; ammonia; corneal endothelial dystrophy; glutamine; lactate

DOI:  https://doi.org/10.3390/cells11020197
Biomedicines. 2021 Dec 23. pii: 28. [Epub ahead of print]10(1):

Unveiling Metabolic Vulnerability and Plasticity of Human Osteosarcoma Stem and Differentiated Cells to Improve Cancer Therapy.

Gerardo Della Sala, Consiglia Pacelli, Francesca Agriesti, Ilaria Laurenzana, Francesco Tucci, Mirko Tamma, Nazzareno Capitanio, Claudia Piccoli.

  Defining the metabolic phenotypes of cancer-initiating cells or cancer stem cells and of their differentiated counterparts might provide fundamental knowledge for improving or developing more effective therapies. In this context we extensively characterized the metabolic profiles of two osteosarcoma-derived cell lines, the 3AB-OS cancer stem cells and the parental MG-63 cells. To this aim Seahorse methodology-based metabolic flux analysis under a variety of conditions complemented with real time monitoring of cell growth by impedentiometric technique and confocal imaging were carried out. The results attained by selective substrate deprivation or metabolic pathway inhibition clearly show reliance of 3AB-OS on glycolysis and of MG-63 on glutamine oxidation. Treatment of the osteosarcoma cell lines with cisplatin resulted in additive inhibitory effects in MG-63 cells depleted of glutamine whereas it antagonized under selective withdrawal of glucose in 3AB-OS cells thereby manifesting a paradoxical pro-survival, cell-cycle arrest in S phase and antioxidant outcome. All together the results of this study highlight that the efficacy of specific metabolite starvation combined with chemotherapeutic drugs depends on the cancer compartment and suggest cautions in using it as a generalizable curative strategy.

Keywords:  cancer stem cell; cisplatin; impedentiometry; metabolic flux analysis; metabolic therapy; mitochondria; oncometabolism; osteosarcoma

DOI:  https://doi.org/10.3390/biomedicines10010028
Mol Ther. 2022 Jan 13. pii: S1525-0016(22)00022-3. [Epub ahead of print]

Exosome derived circTRPS1 promotes malignant phenotype and CD8+ T cell exhaustion in bladder cancer microenvironment through modulating reactive oxygen species equilibrium via GLS1 mediated glutamine metabolism alteration.

Chen Yang, Siqi Wu, Zezhong Mou, Quan Zhou, Xiyu Dai, Yuxi Ou, Xinan Chen, Yiling Chen, Chenyang Xu, Yun Hu, Limin Zhang, Lujia Zou, Shengming Jin, Jimeng Hu, Shanhua Mao, Haowen Jiang.

Circular RNAs (circRNAs) play critical roles in different diseases. Exosomes are important intermediates of intercellular communication. While both have been widely reported in cancers, exosome derived circRNAs are rarely studied. In this work, we identified the differently expressed circRNAs in bladder cancer (BCa) tissue and exosomes through high-throughput sequencing. RNA pull-down, RNA immunoprecipitation and luciferase reporter assay were used to investigate the interactions between specific circRNA, miRNA and mRNA. Wound healing assay, transwell assay, CCK8 assay and colony formation assay were used to study the biological roles in vitro. Metabolomics were used to explore the mechanism of how specific circRNA influenced BCa cells behavior. Flow cytometry was used to study how specific circRNA affected the function of CD8+ T cells in tumor microenvironment. We identified that exosome derived hsa_circ_0085361 (circTRPS1) was correlated with aggressive phenotype of BCa cells via sponging miR-141-3p. Metabolomics and RNA-seq identified GLS1 mediated glutamine metabolism was involved in circTRPS1 mediated alteration. Exosomes derived from circTRPS1 knocked down BCa cells prevented CD8+ T cells from exhaustion and repressed the malignant phenotype of BCa cells. To conclude, exosome derived circTRPS1 from BCa cells can modulate intracellular reactive oxygen species (ROS) balance and CD8+ T cells exhaustion via circTRPS1/miR141-3p/GLS1 axis. Our work may provide a potential biomarker and therapeutic target for BCa.

DOI: https://doi.org/10.1016/j.ymthe.2022.01.022
Metabolites. 2022 Jan 10. pii: 56. [Epub ahead of print]12(1):

Metabolomic Analysis of Carbohydrate and Amino Acid Changes Induced by Hypoxia in Naked Mole-Rat Brain and Liver.

Hang Cheng, Yiming Amy Qin, Rashpal Dhillon, James Dowell, John M Denu, Matthew E Pamenter.

  Hypoxia poses a major physiological challenge for mammals and has significant impacts on cellular and systemic metabolism. As with many other small rodents, naked mole-rats (NMRs; Heterocephalus glaber), who are among the most hypoxia-tolerant mammals, respond to hypoxia by supressing energy demand (i.e., through a reduction in metabolic rate mediated by a variety of cell- and tissue-level strategies), and altering metabolic fuel use to rely primarily on carbohydrates. However, little is known regarding specific metabolite changes that underlie these responses. We hypothesized that NMR tissues utilize multiple strategies in responding to acute hypoxia, including the modulation of signalling pathways to reduce anabolism and reprogram carbohydrate metabolism. To address this question, we evaluated changes of 64 metabolites in NMR brain and liver following in vivo hypoxia exposure (7% O2, 4 h). We also examined changes in matched tissues from similarly treated hypoxia-intolerant mice. We report that, following exposure to in vivo hypoxia: (1) phenylalanine, tyrosine and tryptophan anabolism are supressed both in NMR brain and liver; (2) carbohydrate metabolism is reprogramed in NMR brain and liver, but in a divergent manner; (3) redox state is significantly altered in NMR brain; and (4) the AMP/ATP ratio is elevated in liver. Overall, our results suggest that hypoxia induces significant metabolic remodelling in NMR brain and liver via alterations of multiple metabolic pathways.

Keywords:  AMP; aspartic acid; coenzyme; dopamine; glutamate; glutamine; glutathione; glycogen; pentose phosphate pathway

DOI:  https://doi.org/10.3390/metabo12010056
Sci Adv. 2022 Jan 21. 8(3): eabg6383

Interactions with stromal cells promote a more oxidized cancer cell redox state in pancreatic tumors.

Rupsa Datta, Sharanya Sivanand, Allison N Lau, Logan V Florek, Anna M Barbeau, Jeffrey Wyckoff, Melissa C Skala, Matthew G Vander Heiden.

Access to electron acceptors supports oxidized biomass synthesis and can be limiting for cancer cell proliferation, but how cancer cells overcome this limitation in tumors is incompletely understood. Nontransformed cells in tumors can help cancer cells overcome metabolic limitations, particularly in pancreatic cancer, where pancreatic stellate cells (PSCs) promote cancer cell proliferation and tumor growth. However, whether PSCs affect the redox state of cancer cells is not known. By taking advantage of the endogenous fluorescence properties of reduced nicotinamide adenine dinucleotide and oxidized flavin adenine dinucleotide cofactors we use optical imaging to assess the redox state of pancreatic cancer cells and PSCs and find that direct interactions between PSCs and cancer cells promote a more oxidized state in cancer cells. This suggests that metabolic interaction between cancer cells and PSCs is a mechanism to overcome the redox limitations of cell proliferation in pancreatic cancer.

DOI: https://doi.org/10.1126/sciadv.abg6383
Oncogene. 2022 Jan 22.

Genomic alterations drive metastases formation in pancreatic ductal adenocarcinoma cancer: deciphering the role of CDKN2A and CDKN2B in mediating liver tropism.

Shani Journo, Anat Klein Goldberg, Ethan S Sokol, Lotem Zinger, Metsada Pasmanik-Chor, Boris Sarvin, Dor Simkin, Sivan Fuchs, Tomer Shlomi, Ido Wolf, Tami Rubinek.

Metastases are often the direct cause of death from pancreatic ductal adenocarcinoma (PDAC). The role of genomic alterations (GA) in mediating tropism and metastasis formation by PDAC cells is currently unknown. We aimed to identify GAs predisposing colonization of PDAC cells to the liver and decipher mechanisms enabling this process. In order to reveal specific genes, we studied the frequency of GA in 8,880 local and 7,983 metastatic PDAC samples. We observed differential pattern of GA in the local tumor and specific metastatic sites, with liver metastases characterized by deletion of CDKN2A/B (encoding p16/p15, respectively). The role of CDKN2A/B in promoting liver metastasis was evidenced by enhanced tumorigenic phenotype of p15/p16-deleted PDAC cells when exposed to hepatocytes conditioned media. The liver is characterized by high-ammonia low-glutamine environment and transcriptomic assays indicated unique adaptation of PDAC cells to these conditions, including regulation of genes leading to reduced glutaminolysis, like overexpression of GLUL and reduction in GLS2. Furthermore, metabolic assays indicated an increase in glutamate derived from [U-13C]-glucose in p15/p16-deleted cells. Importantly, these cells thrived under high ammonia condition. These data suggest a unique role for genomic alterations in mediating tropism of PDAC. Among these alterations, p15/16 deletion was identified as a promoter of liver metastases. Further studies indicated a unique role for p15/16 in regulating glutaminolysis. These findings reveal vulnerabilities in PDAC cells, which may pave the way for the development of novel therapeutic strategies aiming at the prevention of liver metastases formation.

DOI: https://doi.org/10.1038/s41388-022-02184-2
Neurochem Int. 2022 Jan 14. pii: S0197-0186(22)00006-7. [Epub ahead of print] 105281

Harnessing oxidative stress for anti-glioma therapy.

Robert P Ostrowski, Emanuela B Pucko.

  Glioma cells use intermediate levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) for growth and invasion, and suppressing these reactive molecules thus may compromise processes that are vital for glioma survival. Increased oxidative stress has been identified in glioma cells, in particular in glioma stem-like cells. Studies have shown that these cells harbor potent antioxidant defenses, although endogenous protection against nitrosative stress remains understudied. The enhancement of oxidative or nitrosative stress offers a potential target for triggering glioma cell death, but whether oxidative and nitrosative stresses can be combined for therapeutic effects requires further research. The optimal approach of harnessing oxidative stress for anti-glioma therapy should include the induction of free radical-induced oxidative damage and the suppression of antioxidant defense mechanisms selectively in glioma cells. However, selective induction of oxidative/nitrosative stress in glioma cells remains a therapeutic challenge, and research into selective drug delivery systems is ongoing. Because of multifactorial mechanisms of glioma growth, progression, and invasion, prospective oncological therapies may include not only therapeutic oxidative/nitrosative stress but also inhibition of oncogenic kinases, antioxidant molecules, and programmed cell death mediators.

Keywords:  Glioblastoma; Glioma; Nitrosative stress; Oxidative stress

DOI:  https://doi.org/10.1016/j.neuint.2022.105281
Evolution. 2022 Jan 19.

Glutamine synthetase evolutionary history revisited: tracing back beyond the Last Universal Common Ancestor.

Gabriela de Carvalho Fernandes, Andreia Carina Turchetto-Zolet, Luciane Maria Pereira Passaglia.

  Glutamine synthetase (GS, EC 6.3.1.2, L-glutamate: ammonia ligase) is an essential enzyme in nitrogen assimilation. It catalyzes glutamine synthesis using glutamate and ammonium with ATP hydrolysis. Four forms of GSs have been described in literature. These enzyme types are discriminated based on their primary and quaternary structures. GS-encoding genes are believed to be of the oldest functioning genes studied, and its evolutionary history was explored in classic studies in the 90's. Here we evaluated GS-homologous sequences from the three life domains to revisit their origins and evolutionary history. There are clear examples of ancient duplications and inter-domain horizontal gene transfers. We present GS-encoding genes as one multigenic family that comprises three distinct groups. Our findings are presented in light of two main hypotheses for GS origins and evolutions, and we argue in favor of gene duplications giving rise to the three genes in LUCA. Type I family is the most diverse one, presenting a subgroup of polyamine metabolizing enzymes, besides many examples of non-catalytic GS-homologs. Many instances of gene loss, duplication, and transfer have occurred after life diversification, contributing to GS complex evolutionary history. This article is protected by copyright. All rights reserved.

Keywords:  gene evolution; glnA; glnII; glnN; glnT; nitrogen

DOI:  https://doi.org/10.1111/evo.14434