bims-glucam 2021-11-07 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021–11–07
thirteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine Imaging: A New Avenue for Glioma Management.
The glutaminase inhibitor telaglenastat enhances the antitumor activity of signal transduction inhibitors everolimus and cabozantinib in models of renal cell carcinoma.
An enhanced mitochondrial function through glutamine metabolism in plasmablast differentiation in systemic lupus erythematosus.
Self-Delivery Nanomedicine for Glutamine-Starvation Enhanced Photodynamic Tumor Therapy.
FAIM regulates autophagy through glutaminolysis in lung adenocarcinoma.
Analysis of Leukemia Cell Metabolism through Stable Isotope Tracing in Mice.
Metabolic profiling of attached and detached metformin and 2-deoxy-D-glucose treated breast cancer cells reveals adaptive changes in metabolome of detached cells.
Amino Acid Homeostasis in Mammalian Cells with a Focus on Amino Acid Transport.
Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape.
Microeconomics of Metabolism: The Warburg Effect as Giffen Behaviour.
Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation.
Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis.
Imbalanced GSH/ROS and sequential cell death.

AJNR Am J Neuroradiol. 2021 Nov 04.

Glutamine Imaging: A New Avenue for Glioma Management.

S Ekici, J A Nye, S G Neill, J W Allen, H-K Shu, C C Fleischer.

The glutamine pathway is emerging as an important marker of cancer prognosis and a target for new treatments. In gliomas, the most common type of brain tumors, metabolic reprogramming leads to abnormal consumption of glutamine as an energy source, and increased glutamine concentrations are associated with treatment resistance and proliferation. A key challenge in the development of glutamine-based biomarkers and therapies is the limited number of in vivo tools to noninvasively assess local glutamine metabolism and monitor its changes. In this review, we describe the importance of glutamine metabolism in gliomas and review the current landscape of translational and emerging imaging techniques to measure glutamine in the brain. These techniques include MRS, PET, SPECT, and preclinical methods such as fluorescence and mass spectrometry imaging. Finally, we discuss the roadblocks that must be overcome before incorporating glutamine into a personalized approach for glioma management.

DOI: https://doi.org/10.3174/ajnr.A7333
PLoS One. 2021 ;16(11): e0259241

The glutaminase inhibitor telaglenastat enhances the antitumor activity of signal transduction inhibitors everolimus and cabozantinib in models of renal cell carcinoma.

Ethan Emberley, Alison Pan, Jason Chen, Rosalyn Dang, Matt Gross, Tony Huang, Weiqun Li, Andrew MacKinnon, Devansh Singh, Natalija Sotirovska, Susanne M Steggerda, Tracy Wang, Francesco Parlati.

Dysregulated metabolism is a hallmark of cancer that manifests through alterations in bioenergetic and biosynthetic pathways to enable tumor cell proliferation and survival. Tumor cells exhibit high rates of glycolysis, a phenomenon known as the Warburg effect, and an increase in glutamine consumption to support the tricarboxylic acid (TCA) cycle. Renal cell carcinoma (RCC) tumors express high levels of glutaminase (GLS), the enzyme required for the first step in metabolic conversion of glutamine to glutamate and the entry of glutamine into the TCA cycle. We found that RCC cells are highly dependent on glutamine for proliferation, and this dependence strongly correlated with sensitivity to telaglenstat (CB-839), an investigational, first-in-class, selective, orally bioavailable GLS inhibitor. Metabolic profiling of RCC cell lines treated with telaglenastat revealed a decrease in glutamine consumption, which was concomitant with a decrease in the production of glutamate and other glutamine-derived metabolites, consistent with GLS inhibition. Treatment of RCC cells with signal transduction inhibitors everolimus (mTOR inhibitor) or cabozantinib (VEGFR/MET/AXL inhibitor) in combination with telaglenastat resulted in decreased consumption of both glucose and glutamine and synergistic anti-proliferative effects. Treatment of mice bearing Caki-1 RCC xenograft tumors with cabozantinib plus telaglenastat resulted in reduced tumor growth compared to either agent alone. Enhanced anti-tumor activity was also observed with the combination of everolimus plus telaglenastat. Collectively, our results demonstrate potent, synergistic, anti-tumor activity of telaglenastat plus signal transduction inhibitors cabozantinib or everolimus via a mechanism involving dual inhibition of glucose and glutamine consumption.

DOI: https://doi.org/10.1371/journal.pone.0259241
Rheumatology (Oxford). 2021 Nov 03. pii: keab824. [Epub ahead of print]

An enhanced mitochondrial function through glutamine metabolism in plasmablast differentiation in systemic lupus erythematosus.

Maiko Hajime Sumikawa, Shigeru Iwata, Mingzeng Zhang, Hiroko Miyata, Masanobu Ueno, Yasuyuki Todoroki, Atsushi Nagayasu, Ryuichiro Kanda, Koshiro Sonomoto, Keiichi Torimoto, Seunghyun Lee, Shingo Nakayamada, Kazuo Yamamoto, Yosuke Okada, Yoshiya Tanaka.

   OBJECTIVE: To evaluate the dysfunction of B cell metabolism and its involvement in SLE pathology.
METHODS: We assessed the expression of metabolic markers of B cells in the peripheral blood of healthy controls (HCs) and SLE patients by using flow cytometry. In vitro, peripheral B cells were isolated from HCs and SLE patients to investigate the metabolic regulation mechanisms involved in their differentiation.
RESULTS: The expression level of DiOc6 (mitochondrial membrane hyperpolarization) was higher in B cells from SLE patients than in HCs, and correlated to the percentage of plasmablasts in CD19+ cells and with SLEDAI, a disease activity score. Stimulation of CD19+ cells with the Toll-like receptor 9 (TLR9) ligand CpG and IFN-α enhanced glycolysis, oxidative phosphorylation (OXPHOS), DiOc6 expression, and plasmablast differentiation in vitro. In the absence of glutamine, both glycolysis and OXPHOS were reduced, and plasmablast differentiation was suppressed, whereas there was no change in the absence of glucose. As glutamine is an important nutrient for protein synthesis, we further investigated the effect of the glutaminase inhibitor BPTES, which inhibits glutamine degradation, on metabolic regulation. BPTES reduced DiOc6 expression, OXPHOS, reactive oxygen species (ROS) production, ATP production, plasmablast differentiation without affecting glycolysis. Metformin inhibited CpG- and IFN-α-induced glutamine uptake, mitochondrial functions and suppressed plasmablast differentiation.
CONCLUSIONS: Mitochondrial dysfunction in B cells is associated with plasmablast differentiation and disease activity in SLE. Enhanced mitochondrial functions mediated by glutamine metabolism are important for plasmablast differentiation, which may be a potential therapeutic target for SLE.

Keywords:  B cell; Glutamine; Glutaminolysis; Immunology; Immunometabolism; Metformin; Mitochondria; SLE; Therapy; plasmablast

DOI:  https://doi.org/10.1093/rheumatology/keab824
Adv Healthc Mater. 2021 Nov 02. e2102038

Self-Delivery Nanomedicine for Glutamine-Starvation Enhanced Photodynamic Tumor Therapy.

Lin-Ping Zhao, Shao-Yi Chen, Rong-Rong Zheng, Ren-Jiang Kong, Xiao-Na Rao, A-Li Chen, Hong Cheng, Da-Wei Zhang, Shi-Ying Li, Xi-Yong Yu.

  Glutamine metabolism of tumor cells plays a crucial role in maintaining cell homeostasis and reducing oxidative damage. Herein, a valid strategy of inhibiting glutamine metabolism is proposed to amplify the oxidative damage of photodynamic therapy (PDT) to tumor cells. Specifically, we develop a drug co-delivery system (designated as CeV) based on chlorine e6 (Ce6) and V9302 via the self-assembly technology. In spite of the strong hydrophobicity of therapeutic agents, the assembled CeV holds a favorable dispersibility in water and an improved cellular uptake capability. Under light irradiation, the internalized CeV is capable of generating abundant ROS for PDT. More importantly, CeV could reduce the uptake of glutamine through V9302-mediated ASCT2 inhibition, leading to a reduced GSH production and an amplified oxidative stress. As a result, CeV has a robust PDT efficacy on tumor inhibition by the blockade of glutamine transport. Notably, CeV exhibits a superiority on tumor suppression over the single treatment as well as the combined administration of Ce6 and V9302, which indicates the advantage of CeV for synergistic treatment. It may serve as a novel nanoplatform for developing drug co-delivery system to improve PDT efficiency by inhibiting cell metabolism. This article is protected by copyright. All rights reserved.

Keywords:  co-delivery; glutamine metabolism; oxidative stress; photodynamic therapy; self-assembly

DOI:  https://doi.org/10.1002/adhm.202102038
Autophagy. 2021 Oct 31. 1-17

FAIM regulates autophagy through glutaminolysis in lung adenocarcinoma.

Tianyu Han, Pengcheng Wang, Yanan Wang, Wenze Xun, Jiapeng Lei, Tao Wang, Zhuo Lu, Mingxi Gan, Wei Zhang, Bentong Yu, Jian-Bin Wang.

  Altered glutamine metabolism is an important aspect of cancer metabolic reprogramming. The GLS isoform GAC (glutaminase C), the rate-limiting enzyme in glutaminolysis, plays a vital role in cancer initiation and progression. Our previous studies demonstrated that phosphorylation of GAC was essential for its high enzymatic activity. However, the molecular mechanisms for GAC in maintaining its high enzymatic activity and protein stability still need to be further clarified. FAIM/FAIM1 (Fas apoptotic inhibitory molecule) is known as an important anti-apoptotic protein, but little is known about its function in tumorigenesis. Here, we found that knocking down FAIM induced macroautophagy/autophagy through suppressing the activation of the MTOR pathway in lung adenocarcinoma. Further studies demonstrated that FAIM could promote the tetramer formation of GAC through increasing PRKCE/PKCε-mediated phosphorylation. What's more, FAIM also stabilized GAC through sequestering GAC from degradation by protease ClpXP. These effects increased the production of α-ketoglutarate, leading to the activation of MTOR. Besides, FAIM also promoted the association of ULK1 and MTOR and this further suppressed autophagy induction. These findings discovered new functions of FAIM and elucidated an important molecular mechanism for GAC in maintaining its high enzymatic activity and protein stability.

Keywords:  Autophagy; Fas apoptosis inhibitory molecule 1; glutaminase C; protein stability; tetramer formation

DOI:  https://doi.org/10.1080/15548627.2021.1987672
Bio Protoc. 2021 Oct 05. 11(19): e4171

Analysis of Leukemia Cell Metabolism through Stable Isotope Tracing in Mice.

Nick van Gastel, Jessica B Spinelli, Marcia C Haigis, David T Scadden.

  Once thought to be a mere consequence of the state of a cell, intermediary metabolism is now recognized as a key regulator of mammalian cell fate and function. In addition, cell metabolism is often disturbed in malignancies such as cancer, and targeting metabolic pathways can provide new therapeutic options. Cell metabolism is mostly studied in cell cultures in vitro, using techniques such as metabolomics, stable isotope tracing, and biochemical assays. Increasing evidence however shows that the metabolic profile of cells is highly dependent on the microenvironment, and metabolic vulnerabilities identified in vitro do not always translate to in vivo settings. Here, we provide a detailed protocol on how to perform in vivo stable isotope tracing in leukemia cells in mice, focusing on glutamine metabolism in acute myeloid leukemia (AML) cells. This method allows studying the metabolic profile of leukemia cells in their native bone marrow niche.

Keywords:  Cancer biology; Cell metabolism; Glutamine; Leukemia; Metabolic tracing; Mouse models

DOI:  https://doi.org/10.21769/BioProtoc.4171
Sci Rep. 2021 Nov 01. 11(1): 21354

Metabolic profiling of attached and detached metformin and 2-deoxy-D-glucose treated breast cancer cells reveals adaptive changes in metabolome of detached cells.

Jernej Repas, Elmar Zügner, Boris Gole, Maruša Bizjak, Uroš Potočnik, Christoph Magnes, Mojca Pavlin.

Anchorage-independent growth of cancer cells in vitro is correlated to metastasis formation in vivo. Metformin use is associated with decreased breast cancer incidence and currently evaluated in cancer clinical trials. The combined treatment with metformin and 2-deoxy-D-glucose (2DG) in vitro induces detachment of viable MDA-MB-231 breast cancer cells that retain their proliferation capacity. This might be important for cell detachment from primary tumors, but the metabolic changes involved are unknown. We performed LC/MS metabolic profiling on separated attached and detached MDA-MB-231 cells treated with metformin and/or 2DG. High 2DG and metformin plus 2DG altered the metabolic profile similarly to metformin, inferring that metabolic changes are necessary but not sufficient while the specific effects of 2DG are crucial for detachment. Detached cells had higher NADPH levels and lower fatty acids and glutamine levels compared to attached cells, supporting the role of AMPK activation and reductive carboxylation in supporting anchorage-independent survival. Surprisingly, the metabolic profile of detached cells was closer to untreated control cells than attached treated cells, suggesting detachment might help cells adapt to energy stress. Metformin treated cells had higher fatty and amino acid levels with lower purine nucleotide levels, which is relevant for understanding the anticancer mechanisms of metformin.

DOI: https://doi.org/10.1038/s41598-021-98642-0
J Nutr. 2021 Oct 27. pii: nxab342. [Epub ahead of print]

Amino Acid Homeostasis in Mammalian Cells with a Focus on Amino Acid Transport.

Stefan Bröer, Gregory Gauthier-Coles.

  Amino acid homeostasis is maintained by import, export, oxidation, and synthesis of nonessential amino acids, and by the synthesis and breakdown of protein. These processes work in conjunction with regulatory elements that sense amino acids or their metabolites. During and after nutrient intake, amino acid homeostasis is dominated by autoregulatory processes such as transport and oxidation of excess amino acids. Amino acid deprivation triggers processes such as autophagy and the execution of broader transcriptional programs to maintain plasma amino acid concentrations. Amino acid transport plays a crucial role in the absorption of amino acids in the intestine, the distribution of amino acids across cells and organs, the recycling of amino acids in the kidney, and the recycling of amino acids after protein breakdown.

Keywords:  ATF4; GCN2; autophagy; mTORC1; solute carrier; transceptor

DOI:  https://doi.org/10.1093/jn/nxab342
Cell Metab. 2021 Nov 02. pii: S1550-4131(21)00486-1. [Epub ahead of print]33(11): 2247-2259.e6

Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape.

Giulia Salvadori, Federica Zanardi, Fabio Iannelli, Riccardo Lobefaro, Claudio Vernieri, Valter D Longo.

  Metastatic tumors remain lethal due to primary/acquired resistance to therapy or cancer stem cell (CSC)-mediated repopulation. We show that a fasting-mimicking diet (FMD) activates starvation escape pathways in triple-negative breast cancer (TNBC) cells, which can be identified and targeted by drugs. In CSCs, FMD lowers glucose-dependent protein kinase A signaling and stemness markers to reduce cell number and increase mouse survival. Accordingly, metastatic TNBC patients with lower glycemia survive longer than those with higher baseline glycemia. By contrast, in differentiated cancer cells, FMD activates PI3K-AKT, mTOR, and CDK4/6 as survival/growth pathways, which can be targeted by drugs to promote tumor regression. FMD cycles also prevent hyperglycemia and other toxicities caused by these drugs. These data indicate that FMD has wide and differential effects on normal, cancer, and CSCs, allowing the rapid identification and targeting of starvation escape pathways and providing a method potentially applicable to many malignancies.

Keywords:  CDK4/6; PI3K/AKT; PKA; cancer stem cells; fasting; fasting-mimicking diet; glucose; mTOR; starvation escape pathways; triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.cmet.2021.10.008
Bull Math Biol. 2021 Oct 31. 83(12): 120

Microeconomics of Metabolism: The Warburg Effect as Giffen Behaviour.

Jumpei F Yamagishi, Tetsuhiro S Hatakeyama.

  Metabolic behaviours of proliferating cells are often explained as a consequence of rational optimization of cellular growth rate, whereas microeconomics formulates consumption behaviours as optimization problems. Here, we pushed beyond the analogy to precisely map metabolism onto the theory of consumer choice. We thereby revealed the correspondence between long-standing mysteries in both fields: the Warburg effect, a seemingly wasteful but ubiquitous strategy where cells favour aerobic glycolysis over more energetically efficient oxidative phosphorylation, and Giffen behaviour, the unexpected consumer behaviour where a good is demanded more as its price rises. We identified the minimal, universal requirements for the Warburg effect: a trade-off between oxidative phosphorylation and aerobic glycolysis and complementarity, i.e. impossibility of substitution for different metabolites. Thus, various hypotheses for the Warburg effect are integrated into an identical optimization problem with the same universal structure. Besides, the correspondence between the Warburg effect and Giffen behaviour implies that oxidative phosphorylation is counter-intuitively stimulated when its efficiency is decreased by metabolic perturbations such as drug administration or mitochondrial dysfunction; the concept of Giffen behaviour bridges the Warburg effect and the reverse Warburg effect. This highlights that the application of microeconomics to metabolism can offer new predictions and paradigms for both biology and economics.

Keywords:  Metabolic systems; Overflow metabolism; Reverse Warburg effect; Theory of consumer choice

DOI:  https://doi.org/10.1007/s11538-021-00952-x
Proc Natl Acad Sci U S A. 2021 Nov 09. pii: e2100050118. [Epub ahead of print]118(45):

Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation.

Katalin Erdélyi, Tamás Ditrói, Henrik J Johansson, Ágnes Czikora, Noémi Balog, Laxmi Silwal-Pandit, Tomoaki Ida, Judit Olasz, Dorottya Hajdú, Zoltán Mátrai, Orsolya Csuka, Koji Uchida, József Tóvári, Olav Engebraten, Takaaki Akaike, Anne-Lise Børresen Dale, Miklós Kásler, Janne Lehtiö, Péter Nagy.

  Basal-like breast cancer (BLBC) is the most aggressive subtype of breast tumors with poor prognosis and limited molecular-targeted therapy options. We show that BLBC cells have a high Cys demand and reprogrammed Cys metabolism. Patient-derived BLBC tumors from four different cohorts exhibited elevated expression of the transsulfuration enzyme cystathione β-synthetase (CBS). CBS silencing (shCBS) made BLBC cells less invasive, proliferate slower, more vulnerable to oxidative stress and cystine (CySSCy) deprivation, prone to ferroptosis, and less responsive to HIF1-α activation under hypoxia. shCBS xenograft tumors grew slower than controls and exhibited impaired angiogenesis and larger necrotic areas. Sulfur metabolite profiling suggested that realigned sulfide/persulfide-inducing functions of CBS are important in BLBC tumor progression. Supporting this, the exclusion of serine, a substrate of CBS for producing Cys but not for producing sulfide/persulfide, did not exacerbate CySSCy deprivation-induced ferroptosis in shCBS BLBC cells. Impaired Tyr phosphorylation was detected in shCBS cells and xenografts, likely due to persulfidation-inhibited phosphatase functions. Overexpression of cystathione γ-lyase (CSE), which can also contribute to cellular sulfide/persulfide production, compensated for the loss of CBS activities, and treatment of shCBS xenografts with a CSE inhibitor further blocked tumor growth. Glutathione and protein-Cys levels were not diminished in shCBS cells or xenografts, but levels of Cys persulfidation and the persulfide-catabolizing enzyme ETHE1 were suppressed. Finally, expression of enzymes of the oxidizing Cys catabolism pathway was diminished, but expression of the persulfide-producing CARS2 was elevated in human BLBC tumors. Hence, the persulfide-producing pathways are major targetable determinants of BLBC pathology that could be therapeutically exploited.

Keywords:  basal-like breast cancer; cystathione β-synthetase; hydrogen sulfide; persulfide; transsulfuration

DOI:  https://doi.org/10.1073/pnas.2100050118
Cell Rep. 2021 Nov 02. pii: S2211-1247(21)01384-X. [Epub ahead of print]37(5): 109911

Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis.

Maria I Matias, Carmen S Yong, Amir Foroushani, Chloe Goldsmith, Cédric Mongellaz, Erdinc Sezgin, Kandice R Levental, Ali Talebi, Julie Perrault, Anais Rivière, Jonas Dehairs, Océane Delos, Justine Bertand-Michel, Jean-Charles Portais, Madeline Wong, Julien C Marie, Ameeta Kelekar, Sandrina Kinet, Valérie S Zimmermann, Ilya Levental, Laurent Yvan-Charvet, Johannes V Swinnen, Stefan A Muljo, Hector Hernandez-Vargas, Saverio Tardito, Naomi Taylor, Valérie Dardalhon.

  Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate.

Keywords:  CAR T cells; DNA methylation; T cell differentiation; TCA cycle; Th1; Treg; lipidome; mitochondrial metabolism; triacylglyceride synthesis; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.celrep.2021.109911
J Biochem Mol Toxicol. 2021 Nov 02. e22942

Imbalanced GSH/ROS and sequential cell death.

Ting Liu, Li Sun, Yubin Zhang, Yonglin Wang, Jiang Zheng.

  Reactive oxygen species (ROS) are produced in cells during metabolic processes. Excessive intracellular ROS may react with large biomolecules, such as DNA, RNA, proteins, and small biomolecules, that is, glutathione (GSH) and unsaturated fatty acids. GSH has physiological functions, including free radical scavenging, anti-oxidation, and electrophile elimination. The disruption of ROS/GSH balance results in the deleterious oxidation and chemical modification of biomacromolecules, which eventually leads to cell-cycle arrest and proliferation inhibition, and even induces cell death. Imbalanced ROS/GSH may result from a direct increase of ROS, consumption of GSH, intracellular oxidoreductase interference, or thioredoxin activity reduction. Some chemicals including arsenic trioxide (ATO), pyrogallol (PG), and carbobenzoxy-Leu-Leu-leucinal (MG132) could also disrupt the balance of GSH and ROS. This article reviews the occurrence and consequences of the imbalance between GSH and ROS and introduces factors responsible for the disruption of cellular ROS and GSH balance, resulting in cell death. "GSH" and "ROS" were used as keywords to search the relevant literaturess.

Keywords:  GSH; ROS; apoptosis; redox balance; stress signaling pathways

DOI:  https://doi.org/10.1002/jbt.22942