bims-glucam 2021-10-31 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021–10–31
nine papers selected by
Sreeparna Banerjee, Middle East Technical University

Adipocytic Glutamine Synthetase Upregulation via Altered Histone Methylation Promotes 5FU Chemoresistance in Peritoneal Carcinomatosis of Colorectal Cancer.
Identification and characterization of a novel glutaminase inhibitor.
Inhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors.
Expression and function of SLC38A5, an amino acid-coupled Na+/H+ exchanger, in triple-negative breast cancer and its relevance to macropinocytosis.
GCN2 adapts protein synthesis to scavenging-dependent growth.
The impact of physiological metabolite levels on serine uptake, synthesis and utilization in cancer cells.
Metabolite discovery through global annotation of untargeted metabolomics data.
Metabolic requirements of the metastatic cascade.
Metabolic reprogramming in cancer: the bridge that connects intracellular stresses and cancer behaviors.

Front Oncol. 2021 ;11 748730

Adipocytic Glutamine Synthetase Upregulation via Altered Histone Methylation Promotes 5FU Chemoresistance in Peritoneal Carcinomatosis of Colorectal Cancer.

Xuan Zhang, Qing Li, Aibei Du, Yifei Li, Qing Shi, Yanrong Chen, Yang Zhao, Bin Wang, Feng Pan.

  The development of resistance to 5-fluorouracil (5FU) chemotherapy is a major handicap for sustained effective treatment in peritoneal carcinomatosis (PC) of colorectal cancer (CRC). Metabolic reprogramming of adipocytes, a component of the tumor microenvironment and the main composition of peritoneum, plays a significant role in drug resistance of PC, with the mechanisms being not fully understood. By performing metabolomics analysis, we identified glutamine (Gln), an important amino acid, inducing resistance to 5FU-triggered tumor suppression of CRC-PC through activating mTOR pathway. Noteworthily, genetic overexpression of glutamine synthetase (GS) in adipocytes increased chemoresistance to 5FU in vitro and in vivo while this effect was reversed by pharmacological blockage of GS. Next, we showed that methionine metabolism were enhanced in amino acid omitted from CRC-PC of GS transgenic (TgGS) mice, increasing intracellular levels of S-carboxymethy-L-cys. Moreover, loss of dimethylation at lysine 4 of histone H3 (H3k4me2) was found in adipocytes in vitro, which may lead to increased expression of GS. Furthermore, biochemical inhibition of lysine specific demethylase 1 (LSD1) restored H3k4me2, thereby reducing GS-induced chemoresistance to 5FU. Our findings indicate that GS upregulation-induced excessive of Gln in adipocytes via altered histone methylation is potential mediator of resistance to 5FU chemotherapy in patients with CRC-PC.

Keywords:  chemoresistance; colorectal cancer; glutamine synthetase; histone methylation; peritoneal carcinomatosis

DOI:  https://doi.org/10.3389/fonc.2021.748730
FEBS Open Bio. 2021 Oct 26.

Identification and characterization of a novel glutaminase inhibitor.

Henning Cederkvist, Shrikant S Kolan, Jonas Aakre Wik, Zeynep Sener, Bjørn Steen Skålhegg.

  In humans, there are two forms of glutaminase (GLS), designated GLS1 and GLS2. These enzymes catalyze the conversion of glutamine to glutamate. GLS1 exists as two isozymes: kidney glutaminase (KGA) and glutaminase C (GAC). Several GLS inhibitors have been identified, of which DON (6-diazo-5-oxonorleucine), BPTES (bis-2-(5-phenylacetamido-1, 3, 4-thiadiazol-2-yl) ethyl sulphide), 968 (5-(3-Bromo-4-(dimethylamino)phenyl)-2,2-dimethyl-2,3,5,6-tetrahydrobenzo[a]phenanthridin-4(1H)-one), and CB839 (Telaglenastat) are the most widely used. However, these inhibitors have variable efficacy, specificity and bioavailability in research and clinical settings, implying the need for novel and improved GLS inhibitors. Based on this need, a diverse library of 28000 compounds from Enamine was screened for inhibition of recombinant, purified GAC. From this library, one inhibitor designated compound 19 (C19) was identified with kinetic features revealing allosteric inhibition of GAC in the µM range. Moreover, C19 inhibits anti-CD3/CD28-induced CD4+ T cell proliferation and cytokine production with similar or greater potency as compared to BPTES. Taken together, our data suggest that C19 has the potential to modulate GLS1 activity and alter metabolic activity of T cells.

Keywords:  BPTES; CB839; CD4+ T cells; GAC; GLS inhibitor; High throughput screening

DOI:  https://doi.org/10.1002/2211-5463.13319
Cell Chem Biol. 2021 Oct 22. pii: S2451-9456(21)00441-4. [Epub ahead of print]

Inhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors.

Kellen Olszewski, Anthony Barsotti, Xiao-Jiang Feng, Milica Momcilovic, Kevin G Liu, Ji-In Kim, Koi Morris, Christophe Lamarque, Jack Gaffney, Xuemei Yu, Jeegar P Patel, Joshua D Rabinowitz, David B Shackelford, Masha V Poyurovsky.

  Efforts to target glucose metabolism in cancer have been limited by the poor potency and specificity of existing anti-glycolytic agents and a poor understanding of the glucose dependence of cancer subtypes in vivo. Here, we present an extensively characterized series of potent, orally bioavailable inhibitors of the class I glucose transporters (GLUTs). The representative compound KL-11743 specifically blocks glucose metabolism, triggering an acute collapse in NADH pools and a striking accumulation of aspartate, indicating a dramatic shift toward oxidative phosphorylation in the mitochondria. Disrupting mitochondrial metabolism via chemical inhibition of electron transport, deletion of the malate-aspartate shuttle component GOT1, or endogenous mutations in tricarboxylic acid cycle enzymes, causes synthetic lethality with KL-11743. Patient-derived xenograft models of succinate dehydrogenase A (SDHA)-deficient cancers are specifically sensitive to KL-11743, providing direct evidence that TCA cycle-mutant tumors are vulnerable to GLUT inhibitors in vivo.

Keywords:  GLUT inhibitor; PDX models; electron transport chain inhibitors; glycolysis; imaging; malate-aspartate shuttle; mitochondrial inhibitors; pharmacology; redox biology; toxicology

DOI:  https://doi.org/10.1016/j.chembiol.2021.10.007
Biochem J. 2021 Oct 27. pii: BCJ20210585. [Epub ahead of print]

Expression and function of SLC38A5, an amino acid-coupled Na+/H+ exchanger, in triple-negative breast cancer and its relevance to macropinocytosis.

Sabarish Ramachandran, Souad Sennoune, Monica Sharma, Muthusamy Thangaraju, Varshini Suresh, Tyler Sniegowski, Yangzom Doma Bhutia, Kevin Pruitt, Vadivel Ganapathy.

  Metabolic reprogramming in cancer necessitates increased amino acid uptake, which is accomplished by upregulation of specific amino acid transporters. However, not all tumors rely on any single amino acid transporter for this purpose. Here we report on the differential upregulation of the amino acid transporter SLC38A5 in triple-negative breast cancer (TNBC). The upregulation is evident in TNBC tumors, conventional and patient-derived xenograft TNBC cell lines, and a mouse model of spontaneous TNBC mammary tumor. The upregulation is confirmed by functional assays. SLC38A5 is an amino acid-dependent Na+/H+ exchanger which transports Na+ and amino acids into cells coupled with H+ efflux. Since cell-surface Na+/H+ exchanger is an established inducer of macropinocytosis, an endocytic process for cellular uptake of bulk fluid and its components, we examined the impact of SLC38A5 on macropinocytosis in TNBC cells. We found that the transport function of SLC38A5 is coupled to induction of macropinocytosis. Surprisingly, the transport function of SLC38A5 is inhibited by amilorides, the well-known inhibitors of Na+/H+ exchanger. Downregulation of SLC38A5 in TNBC cells attenuates serine-induced macropinocytosis and reduces cell proliferation significantly as assessed by multiple methods, but does not induce cell death. The Cancer Genome Atlas database corroborates SLC38A5 upregulation in TNBC. This represents the first report on the selective expression of SLC38A5 in TNBC and its role as an inducer of macropinocytosis, thus revealing a novel, hitherto unsuspected, function for an amino acid transporter that goes beyond amino acid delivery but is still relevant to cancer cell nutrition and proliferation.

Keywords:  breast cancer; cell proliferation; glutamine addiction; intracellular alkalinization; macropinocytosis; one-carbon metabolism

DOI:  https://doi.org/10.1042/BCJ20210585
Cell Syst. 2021 Oct 21. pii: S2405-4712(21)00382-3. [Epub ahead of print]

GCN2 adapts protein synthesis to scavenging-dependent growth.

Michel Nofal, Tim Wang, Lifeng Yang, Connor S R Jankowski, Sophia Hsin-Jung Li, Seunghun Han, Lance Parsons, Alexander N Frese, Zemer Gitai, Tracy G Anthony, Martin Wühr, David M Sabatini, Joshua D Rabinowitz.

  Pancreatic cancer cells with limited access to free amino acids can grow by scavenging extracellular protein. In a murine model of pancreatic cancer, we performed a genome-wide CRISPR screen for genes required for scavenging-dependent growth. The screen identified key mediators of macropinocytosis, peripheral lysosome positioning, endosome-lysosome fusion, lysosomal protein catabolism, and translational control. The top hit was GCN2, a kinase that suppresses translation initiation upon amino acid depletion. Using isotope tracers, we show that GCN2 is not required for protein scavenging. Instead, GCN2 prevents ribosome stalling but without slowing protein synthesis; cells still use all of the limiting amino acids as they emerge from lysosomes. GCN2 also adapts gene expression to the nutrient-poor environment, reorienting protein synthesis away from ribosomes and toward lysosomal hydrolases, such as cathepsin L. GCN2, cathepsin L, and the other genes identified in the screen are potential therapeutic targets in pancreatic cancer.

Keywords:  Cathepsin L; GCN2; PDAC; lysosomes; macropinocytosis; protein scavenging; protein synthesis; translation

DOI:  https://doi.org/10.1016/j.cels.2021.09.014
Nat Commun. 2021 Oct 26. 12(1): 6176

The impact of physiological metabolite levels on serine uptake, synthesis and utilization in cancer cells.

Marc Hennequart, Christiaan F Labuschagne, Mylène Tajan, Steven E Pilley, Eric C Cheung, Nathalie M Legrave, Paul C Driscoll, Karen H Vousden.

Serine is a non-essential amino acid that is critical for tumour proliferation and depletion of circulating serine results in reduced tumour growth and increased survival in various cancer models. While many cancer cells cultured in a standard tissue culture medium depend on exogenous serine for optimal growth, here we report that these cells are less sensitive to serine/glycine depletion in medium containing physiological levels of metabolites. The lower requirement for exogenous serine under these culture conditions reflects both increased de novo serine synthesis and the use of hypoxanthine (not present in the standard medium) to support purine synthesis. Limiting serine availability leads to increased uptake of extracellular hypoxanthine, sparing available serine for other pathways such as glutathione synthesis. Taken together these results improve our understanding of serine metabolism in physiologically relevant nutrient conditions and allow us to predict interventions that may enhance the therapeutic response to dietary serine/glycine limitation.

DOI: https://doi.org/10.1038/s41467-021-26395-5
Nat Methods. 2021 Oct 28.

Metabolite discovery through global annotation of untargeted metabolomics data.

Li Chen, Wenyun Lu, Lin Wang, Xi Xing, Ziyang Chen, Xin Teng, Xianfeng Zeng, Antonio D Muscarella, Yihui Shen, Alexis Cowan, Melanie R McReynolds, Brandon J Kennedy, Ashley M Lato, Shawn R Campagna, Mona Singh, Joshua D Rabinowitz.

Liquid chromatography-high-resolution mass spectrometry (LC-MS)-based metabolomics aims to identify and quantify all metabolites, but most LC-MS peaks remain unidentified. Here we present a global network optimization approach, NetID, to annotate untargeted LC-MS metabolomics data. The approach aims to generate, for all experimentally observed ion peaks, annotations that match the measured masses, retention times and (when available) tandem mass spectrometry fragmentation patterns. Peaks are connected based on mass differences reflecting adduction, fragmentation, isotopes, or feasible biochemical transformations. Global optimization generates a single network linking most observed ion peaks, enhances peak assignment accuracy, and produces chemically informative peak-peak relationships, including for peaks lacking tandem mass spectrometry spectra. Applying this approach to yeast and mouse data, we identified five previously unrecognized metabolites (thiamine derivatives and N-glucosyl-taurine). Isotope tracer studies indicate active flux through these metabolites. Thus, NetID applies existing metabolomic knowledge and global optimization to substantially improve annotation coverage and accuracy in untargeted metabolomics datasets, facilitating metabolite discovery.

DOI: https://doi.org/10.1038/s41592-021-01303-3
Curr Opin Syst Biol. 2021 Dec;pii: 100381. [Epub ahead of print]28

Metabolic requirements of the metastatic cascade.

Stanislav Drapela, Ana P Gomes.

Metastases represent a major cause of cancer-associated deaths. Despite extensive research, targeting metastasis remains the main obstacle in cancer therapy. Therefore, it is of tremendous importance to elucidate the mechanisms that impinge on the different steps of the metastatic cascade. Metabolic plasticity is a cornerstone of the tumorigenic process that not only enables cancer cells to rapidly proliferate but also thrive and retain vitality. Plasticity of the metabolic networks that wire cancer cells is of utmost importance during the metastatic cascade when cancer cells are at their most vulnerable and have to survive in a panoply of inhospitable environments as they make their journey to form metastatic lesions. Here, we highlight which metabolic processes are known to power metastasis formation and lay the foundation for additional work aimed at discovering regulatory nodes of metabolic plasticity that can be used to target metastatic disease.

DOI: https://doi.org/10.1016/j.coisb.2021.100381
Natl Sci Rev. 2020 Aug;7(8): 1270-1273

Metabolic reprogramming in cancer: the bridge that connects intracellular stresses and cancer behaviors.

Yi Zhou, Huiyan Sun, Ying Xu.

Extensive changes in cellular metabolisms have been observed in cancer. They are probably induced by the same intracellular stressor, persistent off-balance in intracellular pH across possibly all adult cancers. It is these altered metabolisms that gives rise to a variety of cancerous behaviors such as continuous cell division, metastasis and drug resistance.

DOI: https://doi.org/10.1093/nsr/nwaa082