bims-glucam 2020-10-04 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2020‒10‒04
ten papers selected by
Sreeparna Banerjee
Middle East Technical University

A facile and sensitive method of quantifying glutaminase binding to its inhibitor CB-839 in tissues.
Take Advantage of Glutamine Anaplerosis, the Kernel of the Metabolic Rewiring in Malignant Gliomas.
Disruption of redox homeostasis for combinatorial drug efficacy in K-Ras tumors as revealed by metabolic connectivity profiling.
Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy.
Brain metabolites in cholinergic and glutamatergic pathways are altered by pancreatic cancer cachexia.
Anticancer strategy targeting the energy metabolism of tumor cells surviving a low-nutrient acidic microenvironment (R1).
Amino Acids and Their Transporters in T Cell Immunity and Cancer Therapy.
SLC38A2 overexpression induces cancer-like metabolic profile and cooperates with SLC1A5 in pan-cancer prognosis.
Macrophage Stimulated by Low Ambient Temperature Hasten Tumor Growth via Glutamine Production.
Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis.

J Genet Genomics. 2020 Jun 16. pii: S1673-8527(20)30093-X. [Epub ahead of print]

A facile and sensitive method of quantifying glutaminase binding to its inhibitor CB-839 in tissues.

Yicheng Chen, Yiqing Zhao, David L Bajor, Zhenghe Wang, J Eva Selfridge.

  Many cancer types reprogram their metabolism to become addicted to glutamine. One of the critical enzymes in the utilization of glutamine in these cells is glutaminase. CB-839 (telaglenastat) is a drug that targets glutaminase that is currently being evaluated in many clinical trials for efficacy in various cancer types that are known to be driven by glutamine metabolism. Despite its use, there are limited assays available for testing the pharmacodynamic on-target effects of CB-839 on the limited, small-volume patient samples that are obtained in early-phase clinical trials. Thus, we developed an assay based on the cellular thermal shift assay technique using AlphaLISA technology to show that CB-839 specifically engages glutaminase in colon cancer cell lines in vitro and in minute quantities of mouse xenograft tumors. Notably, we show that this assay detects CB-839 binding to glutaminase in platelets of patients collected while receiving CB-839 on a clinical trial. This assay may be used to study the pharmacodynamic profile of CB-839 in very small tissue samples obtained from patients on a clinical trial and may be useful in future studies designed to screen other inhibitors of glutaminase.

Keywords:  Cancer; Glutaminase; Method

DOI:  https://doi.org/10.1016/j.jgg.2020.06.001
Biomolecules. 2020 Sep 26. pii: E1370. [Epub ahead of print]10(10):

Take Advantage of Glutamine Anaplerosis, the Kernel of the Metabolic Rewiring in Malignant Gliomas.

Filipa Martins, Luís G Gonçalves, Marta Pojo, Jacinta Serpa.

  Glutamine is a non-essential amino acid that plays a key role in the metabolism of proliferating cells including neoplastic cells. In the central nervous system (CNS), glutamine metabolism is particularly relevant, because the glutamine-glutamate cycle is a way of controlling the production of glutamate-derived neurotransmitters by tightly regulating the bioavailability of the amino acids in a neuron-astrocyte metabolic symbiosis-dependent manner. Glutamine-related metabolic adjustments have been reported in several CNS malignancies including malignant gliomas that are considered 'glutamine addicted'. In these tumors, glutamine becomes an essential amino acid preferentially used in energy and biomass production including glutathione (GSH) generation, which is crucial in oxidative stress control. Therefore, in this review, we will highlight the metabolic remodeling that gliomas undergo, focusing on glutamine metabolism. We will address some therapeutic regimens including novel research attempts to target glutamine metabolism and a brief update of diagnosis strategies that take advantage of this altered profile. A better understanding of malignant glioma cell metabolism will help in the identification of new molecular targets and the design of new therapies.

Keywords:  CNS; cancer metabolism; glutamine-glutamate cycle; malignant gliomas; metabolic adaptation; new metabolic-driven targets

DOI:  https://doi.org/10.3390/biom10101370
Cancer Metab. 2020 ;8 22

Disruption of redox homeostasis for combinatorial drug efficacy in K-Ras tumors as revealed by metabolic connectivity profiling.

Daniela Gaglio, Marcella Bonanomi, Silvia Valtorta, Rohit Bharat, Marilena Ripamonti, Federica Conte, Giulia Fiscon, Nicole Righi, Elisabetta Napodano, Federico Papa, Isabella Raccagni, Seth J Parker, Ingrid Cifola, Tania Camboni, Paola Paci, Anna Maria Colangelo, Marco Vanoni, Christian M Metallo, Rosa Maria Moresco, Lilia Alberghina.

  Abstract: Background: Rewiring of metabolism induced by oncogenic K-Ras in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth. The development of effective anti-cancer treatments targeting metabolism may be facilitated by the identification and rational combinatorial targeting of metabolic pathways.
Methods: We performed mass spectrometric metabolomics analysis in vitro and in vivo experiments to evaluate the efficacy of drugs and identify metabolic connectivity.
Results: We show that K-Ras-mutant lung and colon cancer cells exhibit a distinct metabolic rewiring, the latter being more dependent on respiration. Combined treatment with the glutaminase inhibitor CB-839 and the PI3K/aldolase inhibitor NVP-BKM120 more consistently reduces cell growth of tumor xenografts. Maximal growth inhibition correlates with the disruption of redox homeostasis, involving loss of reduced glutathione regeneration, redox cofactors, and a decreased connectivity among metabolites primarily involved in nucleic acid metabolism.
Conclusions: Our findings open the way to develop metabolic connectivity profiling as a tool for a selective strategy of combined drug repositioning in precision oncology.

Keywords:  Combinatorial drug treatment; Glutamine; Glycolysis; Metabolic cancer therapy; Metabolic connectivity; Metabolic rewiring; Metabolic signature; Precision oncology

DOI:  https://doi.org/10.1186/s40170-020-00227-4
Protein Cell. 2020 Oct 01.

Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy.

Pranavi Koppula, Li Zhuang, Boyi Gan.

  The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers. Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation. However, cancer cells with high expression of SLC7A11 (SLC7A11high) also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming, leading to glucose- and glutamine-dependency in SLC7A11high cancer cells, which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11high cancer. In this review, we summarize diverse regulatory mechanisms of SLC7A11 in cancer, discuss ferroptosis-dependent and -independent functions of SLC7A11 in promoting tumor development, explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells, and conceptualize therapeutic strategies to target SLC7A11 in cancer treatment. This review will provide the foundation for further understanding SLC7A11 in ferroptosis, nutrient dependency, and tumor biology and for developing novel effective cancer therapies.

Keywords:  SLC7A11; cancer therapy; cysteine; cystine; ferroptosis; nutrient dependency; xCT

DOI:  https://doi.org/10.1007/s13238-020-00789-5
J Cachexia Sarcopenia Muscle. 2020 Oct 02.

Brain metabolites in cholinergic and glutamatergic pathways are altered by pancreatic cancer cachexia.

Paul T Winnard, Santosh Kumar Bharti, Raj Kumar Sharma, Balaji Krishnamachary, Yelena Mironchik, Marie-France Penet, Michael G Goggins, Anirban Maitra, Ihab Kamel, Karen M Horton, Michael A Jacobs, Zaver M Bhujwalla.

  BACKGROUND: Cachexia is a major cause of morbidity in pancreatic ductal adenocarcinoma (PDAC) patients. Our purpose was to understand the impact of PDAC-induced cachexia on brain metabolism in PDAC xenograft studies, to gain new insights into the causes of cachexia-induced morbidity. Changes in mouse and human plasma metabolites were characterized to identify underlying causes of brain metabolic changes.METHODS: We quantified metabolites, detected with high-resolution 1 H magnetic resonance spectroscopy, in the brain and plasma of normal mice (n = 10) and mice bearing cachexia (n = 10) or non-cachexia (n = 9) inducing PDAC xenografts as well as in human plasma obtained from normal individuals (n = 24) and from individuals with benign pancreatic disease (n = 20) and PDAC (n = 20). Statistical significance was defined as a P value ≤0.05.
RESULTS: The brain metabolic signature of cachexia-inducing PDAC was characterized by a significant depletion of choline of -27% and -21% as well as increases of glutamine of 13% and 9% and formate of 21% and 14%, relative to normal controls and non-cachectic tumour-bearing mice, respectively. Good to moderate correlations with percent weight change were found for choline (r = 0.70), glutamine (r = -0.58), and formate (r = -0.43). Significant choline depletion of -38% and -30%, relative to normal controls and non-cachectic tumour-bearing mice, respectively, detected in the plasma of cachectic mice likely contributed to decreased brain choline in cachectic mice. Similarly, relative to normal controls and patients with benign disease, choline levels in human plasma samples of PDAC patients were significantly lower by -12% and -20% respectively. A comparison of plasma metabolites from PDAC patients with and without weight loss identified significant changes in glutamine metabolism.
CONCLUSIONS: Disturbances in metabolites of the choline/cholinergic and glutamine/glutamate/glutamatergic neurotransmitter pathways may contribute to morbidity. Metabolic normalization may provide strategies to reduce morbidity. The human plasma metabolite changes observed may lead to the development of companion diagnostic markers to detect PDAC and PDAC-induced cachexia.

Keywords:  Brain and plasma 1H MR spectroscopy; Cachexia; Human pancreatic cancer xenografts; Human plasma; Metabolites

DOI:  https://doi.org/10.1002/jcsm.12621
Mol Metab. 2020 Sep 30. pii: S2212-8778(20)30167-8. [Epub ahead of print] 101093

Anticancer strategy targeting the energy metabolism of tumor cells surviving a low-nutrient acidic microenvironment (R1).

Yuki Maeda, Ryota Kikuchi, Junichiro Kawagoe, Takao Tsuji, Nobuyuki Koyama, Kazuhiro Yamaguchi, Hiroyuki Nakamura, Kazutetsu Aoshiba.

  OBJECTIVE: Tumor cells experience hypoxia, acidosis, and hypoglycemia. Metabolic adaptation to a glucose shortage is essential to maintain tumor cell survival because of their high glucose requirement. This study aimed to study the hypothesis that acidosis might promote tumor survival during a glucose shortage and if so, to explore a novel drug targeting metabolic vulnerability to glucose shortage.METHODS: Cell survival and bioenergetics metabolism were assessed in lung cancer cell lines. Our in-house small-molecule compounds were screened to identify those that kill cancer cells under low-glucose conditions. Cytotoxicity against non-cancerous cells was also assessed. Tumor growth was evaluated in vivo using a mouse engraft model.
RESULTS: Acidosis limited the cellular consumption of glucose and ATP, causing tumor cells to enter a metabolically dormant but energetically economic state, which promoted tumor cell survival during glucose deficiency. We identified ESI-09, a previously known exchange protein directly activated by cAMP (EAPC) inhibitor, as an anticancer compound that inhibited cancer cells under low-glucose conditions, even when associated with acidosis. Bioenergetic studies showed that independent of EPAC inhibition, ESI-09 was a safer mitochondrial uncoupler than a classical uncoupler and created a futile cycling of mitochondrial respiration leading to decreased ATP production, increased ATP dissipation, and fuel scavenging. Accordingly, ESI-09 exhibited more cytotoxic effects under low-glucose conditions than under normal glucose conditions. ESI-09 was also more effective than actively proliferating cells on quiescent glucose-restricted cells. Cisplatin showed opposite effects. ESI-09 inhibited tumor growth in lung-cancer engraft mice.
CONCLUSIONS: This study highlights the acidosis-induced promotion of tumor survival during glucose shortage and demonstrates that ESI-09 is a novel potent anticancer mitochondrial uncoupler that targets a metabolic vulnerability to glucose shortage even when associated with acidosis. The higher cytotoxicity under lower than normal glucose conditions suggests that ESI-09 is safer than conventional chemotherapy, can target the metabolic vulnerability of tumor cells to low-glucose stress, and is applicable to many cancer cell types.

Keywords:  acidosis; glucose; lung cancer; mitochondrion; uncoupler

DOI:  https://doi.org/10.1016/j.molmet.2020.101093
Mol Cell. 2020 Sep 22. pii: S1097-2765(20)30614-6. [Epub ahead of print]

Amino Acids and Their Transporters in T Cell Immunity and Cancer Therapy.

Weimin Wang, Weiping Zou.

  Metabolism reprogramming is critical for both cancer progression and effective immune responses in the tumor microenvironment. Amino acid metabolism in different cells and their cross-talk shape tumor immunity and therapy efficacy in patients with cancer. In this review, we focus on multiple amino acids and their transporters, solute carrier (SLC) members. We discuss their involvement in regulation of immune responses in the tumor microenvironment and assess their associations with cancer immunotherapy, chemotherapy, and radiation therapy, and we review their potential as targets for cancer therapy. We stress the necessity to understand individual amino acids and their transporters in different cell subsets, the molecular intersection between amino acid metabolism, and effective T cell immunity and its relevance in cancer therapies.

Keywords:  CD8(+) T cell; amino acid; cancer; checkpoint blockade; immunotherapy; metabolism; solute carriers

DOI:  https://doi.org/10.1016/j.molcel.2020.09.006
Chem Asian J. 2020 Sep 29.

SLC38A2 overexpression induces cancer-like metabolic profile and cooperates with SLC1A5 in pan-cancer prognosis.

Meng-Sen Huang, Jen-Hsuan Chang, Wen-Ching Lin, Yu-Hsiang Cheng, Fu-An Li, Ching-Shu Suen, Ming-Jing Hwang, Chung-Ke Chang, Kurt Yun Mou.

  Cancer cells have dramatically increased demands for energy as well as biosynthetic precursors to fuel their restless growth. Enhanced glutaminolysis is a hallmark of cancer metabolism which fulfills these needs. Two glutamine transporters, SLC1A5 and SLC38A2, have been previously reported to promote glutaminolysis in cancer with controversial perspectives. In this study, we harnessed the proximity labeling reaction to map the protein interactome using mass spectrometry-based proteomics and discovered a potential protein-protein interaction between SLC1A5 and SLC38A2. The SLC1A5/SLC38A2 interaction was further confirmed by bimolecular fluorescence complementation assay. We further investigated the metabolic influence of SLC1A5 and SLC38A2 overexpression in human cells, respectively, and found that only SLC38A2, but not SLC1A5, resulted in a cancer-like metabolic profile, where the intracellular concentrations of essential amino acids and lactate were significantly increased as quantified by nuclear magnetic resonance spectroscopy. Finally, we analyzed the 5-year survival rates in a large pan-cancer cohort and found that the SLC1A5hi/SLC38A2lo group did not relate to a poor survival rate, whereas the SLC1A5lo/SLC38A2hi group significantly aggravated the lethality. Intriguingly, the SLC1A5hi/SLC38A2hi group resulted in an even worse prognosis, suggesting a cooperative effect between SLC1A5 and SCL38A2. Our data suggest that SLC38A2 plays a dominant role in reprogramming the cancer-like metabolism and promoting the cancer progression, whereas SLC1A5 may augment this effect when co-overexpressed with SLC38A2. We propose a model to explain the relationship between SLC1A5, SLC38A2 and SCL7A5, and discuss their impact on glutaminolysis and mTOR signaling.

Keywords:  NMR metabolomics; cancer prognosis; glutamine transporters; mass spectrometric proteomics; proximity labeling

DOI:  https://doi.org/10.1002/asia.202001056
Biomedicines. 2020 Sep 26. pii: E381. [Epub ahead of print]8(10):

Macrophage Stimulated by Low Ambient Temperature Hasten Tumor Growth via Glutamine Production.

Eun-Ji Lee, Tae-Wook Chung, Keuk-Jun Kim, Boram Bae, Bo-Sung Kim, Suhkmann Kim, Dongryeol Ryu, Sung-Jin Bae, Ki-Tae Ha.

  Ambient temperature can regulate the immune response and affect tumor growth. Although thermoneutral caging reduces tumor growth via immune activation, little attention has been paid to the tumorigenic effect of low temperature. In the present study, tumor growth was higher at low ambient temperature (4 °C for 8 h/d) than at the standard housing temperature (22 °C) in allograft models. Low temperature-stimulated tumor growth in mice was reduced by monocyte depletion using clodronate liposomes. Proliferation was considerably greater in cancer cells treated with 33 °C-cultured RAW264.7 cell-conditioned media (33CM) than in cells treated with 37 °C-cultured RAW264.7 cell-conditioned media (37CM). Additionally, glutamine levels were markedly higher in 33CM-treated cells than in 37CM-treated cells. We further confirmed that the addition of glutamine into 37CM enhanced its effects on cancer cell proliferation and glutamine uptake inhibition ameliorated the accelerated proliferation induced by 33CM. Consistently, the inhibition of glutamine uptake in the allograft model exposed to low temperature, effectively reduced tumor volume and weight. Collectively, these data suggest that the secretion and utilization of glutamine by macrophages and cancer cells, respectively, are key regulators of low temperature-enhanced cancer progression in the tumor microenvironment.

Keywords:  cancer; glutamine; glutamine synthetase; low temperature; macrophage

DOI:  https://doi.org/10.3390/biomedicines8100381
Redox Biol. 2020 Sep 12. pii: S2213-2317(20)30924-1. [Epub ahead of print]37 101719

Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis.

Ok-Seon Kwon, Eun-Ji Kwon, Hyeon-Joon Kong, Jeong-Yoon Choi, Yun-Jeong Kim, Eun-Woo Lee, Wankyu Kim, Haeseung Lee, Hyuk-Jin Cha.

  Erastin, a synthetic lethal compound against cancer expressing an oncogenic RAS, inhibits cystine/glutamate antiporters and causes ferroptosis. However, despite recent evidence for the mechanisms underlying ferroptosis, molecular biomarkers of erastin-dependent ferroptosis have not been identified. Here, we employed isogenic lung cancer cell models to show that a redox imbalance leads to glutathione depletion and ferroptosis. Subsequent transcriptome analysis of pan-cancer cell lines revealed that the activity of transcription factors, including NRF2 and AhR, serve as important markers of erastin resistance. Based on the integrated expression of genes in the nuclear receptor meta-pathway (NRM), we constructed an NRM model and validated its robustness using an independent pharmacogenomics dataset. The NRM model was further evaluated by sensitivity tests on nine cancer cell lines for which erastin sensitivities had not been determined. Our pharmacogenomics approach has the potential to pave the way for the efficient classification of patients for therapeutic intervention using erastin.

Keywords:  Aryl hydrocarbon receptor; Drug response biomarker; Drug sensitivity prediction; Elastic net; Erastin; Ferroptosis; NRF2; Redox imbalance

DOI:  https://doi.org/10.1016/j.redox.2020.101719