bims-glucam 2020-11-01 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2020‒11‒01
nine papers selected by
Sreeparna Banerjee
Middle East Technical University

Metabolic plasticity of IDH1-mutant glioma cell lines is responsible for low sensitivity to glutaminase inhibition.
Brain tumor stem cell dependence on glutaminase reveals a metabolic vulnerability through the amino acid deprivation response pathway.
Macrophage-derived glutamine boosts satellite cells and muscle regeneration.
Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression.
Targeting subtype-specific metabolic preferences in nucleotide biosynthesis inhibits tumor growth in a breast cancer model.
Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies.
Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties.
Simulating Multiple Substrate-Binding Events by γ-Glutamyltransferase Using Accelerated Molecular Dynamics.
Sublethal exposure of small few-layer graphene promotes metabolic alterations in human skin cells.

Cancer Metab. 2020 ;8 23

Metabolic plasticity of IDH1-mutant glioma cell lines is responsible for low sensitivity to glutaminase inhibition.

Victor Ruiz-Rodado, Adrian Lita, Tyrone Dowdy, Orieta Celiku, Alejandra Cavazos Saldana, Herui Wang, Chun Zhang Yang, Raj Chari, Aiguo Li, Wei Zhang, Hua Song, Meili Zhang, Susie Ahn, Dionne Davis, Xiang Chen, Zhengping Zhuang, Christel Herold-Mende, Kylie J Walters, Mark R Gilbert, Mioara Larion.

  Background: Targeting glutamine metabolism in cancer has become an increasingly vibrant area of research. Mutant IDH1 (IDH1 mut ) gliomas are considered good candidates for targeting this pathway because of the contribution of glutamine to their newly acquired function: synthesis of 2-hydroxyglutarate (2HG).Methods: We have employed a combination of 13C tracers including glutamine and glucose for investigating the metabolism of patient-derived IDH1 mut glioma cell lines through NMR and LC/MS. Additionally, genetic loss-of-function (in vitro and in vivo) approaches were performed to unravel the adaptability of these cell lines to the inhibition of glutaminase activity.
Results: We report the adaptability of IDH1 mut cells' metabolism to the inhibition of glutamine/glutamate pathway. The glutaminase inhibitor CB839 generated a decrease in the production of the downstream metabolites of glutamate, including those involved in the TCA cycle and 2HG. However, this effect on metabolism was not extended to viability; rather, our patient-derived IDH1 mut cell lines display a metabolic plasticity that allows them to overcome glutaminase inhibition.
Conclusions: Major metabolic adaptations involved pathways that can generate glutamate by using alternative substrates from glutamine, such as alanine or aspartate. Indeed, asparagine synthetase was upregulated both in vivo and in vitro revealing a new potential therapeutic target for a combinatory approach with CB839 against IDH1 mut gliomas.

Keywords:  13C tracing; AGI5198; CB839; Gliomas; Glutaminase; IDH1-mutant

DOI:  https://doi.org/10.1186/s40170-020-00229-2
Cancer Res. 2020 Oct 26. pii: canres.3923.2019. [Epub ahead of print]

Brain tumor stem cell dependence on glutaminase reveals a metabolic vulnerability through the amino acid deprivation response pathway.

Ian J Restall, Orsolya Cseh, Laura M Richards, Trevor J Pugh, H Artee Luchman, Samuel Weiss.

Cancer cells can metabolize glutamine to replenish TCA cycle intermediates, leading to a dependence on glutaminolysis for cell survival. However, a mechanistic understanding of the role that glutamine metabolism has on the survival of glioblastoma (GBM) brain tumor stem cells (BTSC) has not yet been elucidated. Here we report that, across a panel of 19 glioblastoma BTSC lines, inhibition of glutaminase (GLS) showed a variable response from complete blockade of cell growth to absolute resistance. Surprisingly, BTSC sensitivity to GLS inhibition was a result of reduced intracellular glutamate triggering the amino acid deprivation response (AADR) and not due to the contribution of glutaminolysis to the TCA cycle. Moreover, BTSC sensitivity to GLS inhibition negatively correlated with expression of the astrocytic glutamate transporters EAAT1 and EAAT2. Blocking glutamate transport in BTSCs with high EAAT1/EAAT2 expression rendered cells susceptible to GLS inhibition, triggering the AADR and limiting cell growth. These findings uncover a unique metabolic vulnerability in BTSCs and support the therapeutic targeting of upstream activators and downstream effectors of the AADR pathway in GBM. Moreover, they demonstrate that gene expression patterns reflecting the cellular hierarchy of the tissue of origin can alter the metabolic requirements of the cancer stem cell population.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-3923
Nature. 2020 Oct 28.

Macrophage-derived glutamine boosts satellite cells and muscle regeneration.

Min Shang, Federica Cappellesso, Ricardo Amorim, Jens Serneels, Federico Virga, Guy Eelen, Stefania Carobbio, Melvin Y Rincon, Pierre Maechler, Katrien De Bock, Ping-Chih Ho, Marco Sandri, Bart Ghesquière, Peter Carmeliet, Mario Di Matteo, Emanuele Berardi, Massimiliano Mazzone.

Muscle regeneration is sustained by infiltrating macrophages and the consequent activation of satellite cells1-4. Macrophages and satellite cells communicate in different ways1-5, but their metabolic interplay has not been investigated. Here we show, in a mouse model, that muscle injuries and ageing are characterized by intra-tissue restrictions of glutamine. Low levels of glutamine endow macrophages with the metabolic ability to secrete glutamine via enhanced glutamine synthetase (GS) activity, at the expense of glutamine oxidation mediated by glutamate dehydrogenase 1 (GLUD1). Glud1-knockout macrophages display constitutively high GS activity, which prevents glutamine shortages. The uptake of macrophage-derived glutamine by satellite cells through the glutamine transporter SLC1A5 activates mTOR and promotes the proliferation and differentiation of satellite cells. Consequently, macrophage-specific deletion or pharmacological inhibition of GLUD1 improves muscle regeneration and functional recovery in response to acute injury, ischaemia or ageing. Conversely, SLC1A5 blockade in satellite cells or GS inactivation in macrophages negatively affects satellite cell functions and muscle regeneration. These results highlight the metabolic crosstalk between satellite cells and macrophages, in which macrophage-derived glutamine sustains the functions of satellite cells. Thus, the targeting of GLUD1 may offer therapeutic opportunities for the regeneration of injured or aged muscles.

DOI: https://doi.org/10.1038/s41586-020-2857-9
Cancer Discov. 2020 Oct 30. pii: CD-20-0775. [Epub ahead of print]

Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression.

Ralph Francescone, Débora Barbosa Vendramini-Costa, Janusz Franco-Barraza, Jessica Wagner, Alexander Muir, Allison N Lau, Linara Gabitova, Tatiana Pazina, Sapna Gupta, Tiffany Luong, Dustin Rollins, Ruchi Malik, Roshan J Thapa, Diana Restifo, Yan Zhou, Kathy Q Cai, Harvey H Hensley, Yinfei Tan, Warren D Kruger, Karthik Devarajan, Siddharth Balachandran, Andres J Klein-Szanto, Huamin Wang, Wafik S El-Deiry, Matthew G Vander Heiden, Suraj Peri, Kerry S Campbell, Igor Astsaturov, Edna Cukierman.

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multi-plex data from patient tissue, three-dimensional co-culturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1+ cancer-associated fibroblasts (CAFs) support PDAC survival, through a NetG1 mediated effect on glutamate/glutamine metabolism. Also, NetG1+ CAFs are intrinsically immunosuppressive and inhibit NK cell mediated killing of tumor cells. These pro-tumor functions are controlled by a signaling circuit downstream to NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutralizing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC.

DOI: https://doi.org/10.1158/2159-8290.CD-20-0775
Cancer Res. 2020 Oct 28. pii: canres.1666.2020. [Epub ahead of print]

Targeting subtype-specific metabolic preferences in nucleotide biosynthesis inhibits tumor growth in a breast cancer model.

Martin P Ogrodzinski, Shao Thing Teoh, Sophia Y Lunt.

Investigating metabolic rewiring in cancer can lead to the discovery of new treatment strategies for breast cancer subtypes that currently lack targeted therapies. In this study, we used MMTV-Myc-driven tumors to model breast cancer heterogeneity, investigating the metabolic differences between two histological subtypes, the epithelial-mesenchymal transition (EMT) and the papillary subtypes. A combination of genomic and metabolomic techniques identified differences in nucleotide metabolism between EMT and papillary subtypes: EMT tumors preferentially used the nucleotide salvage pathway, while papillary tumors preferred de novo nucleotide biosynthesis. CRISPR/Cas9 gene editing and mass spectrometry-based methods revealed that targeting the preferred pathway in each subtype resulted in greater metabolic impact than targeting the non-preferred pathway. Knocking out the preferred nucleotide pathway in each subtype has a deleterious effect on in vivo tumor growth, whereas knocking out the non-preferred pathway has a lesser effect or may even result in increased tumor growth. Collectively, these data suggest that significant differences in metabolic pathway utilization distinguish EMT and papillary subtypes of breast cancer and identify said pathways as a means to enhance subtype-specific diagnoses and treatment strategies.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-1666
Front Oncol. 2020 ;10 572722

Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies.

Ruiyuan Xu, Jinshou Yang, Bo Ren, Huanyu Wang, Gang Yang, Yuan Chen, Lei You, Yupei Zhao.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies with an extremely poor prognosis. Energy metabolism reprogramming, an emerging hallmark of cancer, has been implicated in the tumorigenesis and development of pancreatic cancer. In addition to well-elaborated enhanced glycolysis, investigating the role of reprogramming of amino acid metabolism has sparked great interests in recent years. The rewiring amino acid metabolism orchestrated by genetic alterations contributes to pancreatic cancer malignant characteristics including cell proliferation, invasion, metastasis, angiogenesis and redox balance. In the unique hypoperfused and nutrient-deficient tumor microenvironment (TME), the interactions between cancer cells and stromal components and salvaging processes including autophagy and macropinocytosis play critical roles in fulfilling the metabolic requirements and supporting growth of PDAC. In this review, we elucidate the recent advances in the amino acid metabolism reprogramming in pancreatic cancer and the mechanisms of amino acid metabolism regulating PDAC progression, which will provide opportunities to develop promising therapeutic strategies.

Keywords:  amino acid metabolism; angiogenesis; metastasis; pancreatic cancer; redox balance; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2020.572722
J Med Chem. 2020 Oct 29.

Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties.

Michael J Soth, Kang Le, Maria Emilia Di Francesco, Matthew M Hamilton, Gang Liu, Jason P Burke, Chris L Carroll, Jeffrey J Kovacs, Jennifer P Bardenhagen, Christopher A Bristow, Mario Cardozo, Barbara Czako, Elisa de Stanchina, Ningping Feng, Jill R Garvey, Jason P Gay, Mary K Geck Do, Jennifer Greer, Michelle Han, Angela Harris, Zachary Herrera, Sha Huang, Virginia Giuliani, Yongying Jiang, Sarah B Johnson, Troy A Johnson, Zhijun Kang, Paul G Leonard, Zhen Liu, Timothy McAfoos, Meredith Miller, Pietro Morlacchi, Robert A Mullinax, Wylie S Palmer, Jihai Pang, Norma Rogers, Charles M Rudin, Hannah E Shepard, Nakia D Spencer, Jay Theroff, Qi Wu, Alan Xu, Ju Anne Yau, Giulio Draetta, Carlo Toniatti, Timothy P Heffernan, Philip Jones.

Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.

DOI: https://doi.org/10.1021/acs.jmedchem.0c01398
J Phys Chem B. 2020 Oct 28.

Simulating Multiple Substrate-Binding Events by γ-Glutamyltransferase Using Accelerated Molecular Dynamics.

Francesco Oliva, Jose C Flores-Canales, Stefano Pieraccini, Carlo F Morelli, Maurizio Sironi, Birgit Schiøtt.

γ-Glutamyltransferase (GGT) is an enzyme that uses γ-glutamyl compounds as substrates and catalyzes their transfer to a water molecule or an acceptor substrate with varied physiological function in bacteria, plants, and animals. Crystal structures of GGT are known for different species and in different states of the chemical reaction; however, the structural dynamics of the substrate binding to the catalytic site of GGT are unknown. Here, we modeled Escherichia coli GGT's glutamine binding by using a swarm of accelerated molecular dynamics (aMD) simulations. Characterization of multiple binding events identified three structural binding motifs composed of polar residues in the binding pocket that govern glutamine binding into the active site. Simulated open and closed conformations of a lid-loop protecting the binding cavity suggest its role as a gating element by allowing or blocking substrates entry into the binding pocket. Partially open states of the lid-loop are accessible within thermal fluctuations, while the estimated free energy cost of a complete open state is 2.4 kcal/mol. Our results suggest that both specific electrostatic interactions and GGT conformational dynamics dictate the molecular recognition of substrate-GGT complexes.

DOI: https://doi.org/10.1021/acs.jpcb.0c06907
Sci Rep. 2020 Oct 27. 10(1): 18407

Sublethal exposure of small few-layer graphene promotes metabolic alterations in human skin cells.

Javier Frontiñan-Rubio, M Victoria Gomez, Viviana Jehová González, Mario Durán-Prado, Ester Vázquez.

Small few-layer graphene (sFLG), a novel small-sized graphene-related material (GRM), can be considered as an intermediate degradation product of graphene. GRMs have a promising present and future in the field of biomedicine. However, safety issues must be carefully addressed to facilitate their implementation. In the work described here, the effect of sub-lethal doses of sFLG on the biology of human HaCaT keratinocytes was examined. A one-week treatment of HaCaTs with sub-lethal doses of sFLG resulted in metabolome remodeling, dampening of the mitochondrial function and a shift in the redox state to pro-oxidant conditions. sFLG raises reactive oxygen species and calcium from 24 h to one week after the treatment and this involves the activation of NADPH oxidase 1. Likewise, sFLG seems to induce a shift from oxidative phosphorylation to glycolysis and promotes the use of glutamine as an alternative source of energy. When sub-toxic sFLG exposure was sustained for 30 days, an increase in cell proliferation and mitochondrial damage were observed. Further research is required to unveil the safety of GRMs and degradation-derived products before their use in the workplace and in practical applications.

DOI: https://doi.org/10.1038/s41598-020-75448-0