bims-glucam 2021-12-19 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021–12–19
thirteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer.
Impact of monomeric and aggregated wild-type and A30P/A53T double-mutant α-synuclein on antioxidant mechanism and glutamate metabolic profile of cultured astrocytes.
An RNA-RNA crosstalk network involving HMGB1 and RICTOR facilitates hepatocellular carcinoma tumorigenesis by promoting glutamine metabolism and impedes immunotherapy by PD-L1+ exosomes activity.
ATG12 deficiency results in intracellular glutamine depletion, abrogation of tumor hypoxia and a favorable prognosis in cancer.
Anorexia disrupts glutamate-glutamine homeostasis associated with astrocytes in the prefrontal cortex of young female rats.
Oncogenic Gq/11 signaling acutely drives and chronically sustains metabolic reprogramming in uveal melanoma.
Integrated Metabolic Profiling and Transcriptional Analysis Reveals Therapeutic Modalities for Targeting Rapidly Proliferating Breast Cancers.
Recent Metabolomics Analysis in Tumor Metabolism Reprogramming.
Cell line-directed breast cancer research based on glucose metabolism status.
Defining the landscape of metabolic dysregulations in cancer metastasis.
Governing glutaminolysis by regulation of glutaminase succinylation.
Physiological and Pathophysiological Role of Cysteine Metabolism in Human Metabolic Syndrome.
Tumor metabolism: metabolic alterations and heterogeneity in cancer progression.

J Exp Clin Cancer Res. 2021 Dec 14. 40(1): 393

Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer.

Liwei Lang, Fang Wang, Zhichun Ding, Xiangdong Zhao, Reid Loveless, Jin Xie, Chloe Shay, Peng Qiu, Yonggang Ke, Nabil F Saba, Yong Teng.

   BACKGROUND: Alterations in metabolism are one of the emerging hallmarks of cancer cells and targeting dysregulated cancer metabolism provides a new approach to developing more selective therapeutics. However, insufficient blockade critical metabolic dependencies of cancer allows the development of metabolic bypasses, thus limiting therapeutic benefits.
METHODS: A series of head and neck squamous cell carcinoma (HNSCC) cell lines and animal models were used to determine the efficacy of CPI-613 and CB-839 when given alone or in combination. Glutaminase 1 (GLS1) depletion was achieved by lentiviral shRNAs. Cell viability and apoptosis were determined in HNSCC cells cultured in 2D culture dish and SeedEZ™ 3D scaffold. Molecular alterations were examined by Western blotting and immunohistochemistry. Metabolic changes were assessed by glucose uptake, lactate production, glutathione levels, and oxygen consumption rate.
RESULTS: We show here that HNSCC cells display strong addiction to glutamine. CPI-613, a novel lipoate analog, redirects cellular activity towards tumor-promoting glutaminolysis, leading to low anticancer efficacy in HNSCC cells. Mechanistically, CPI-613 inhibits the tricarboxylic acid cycle by blocking the enzyme activities of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, which upregulates GLS1 and eventually promotes the compensatory role of glutaminolysis in cancer cell survival. Most importantly, the addition of a GLS1 inhibitor CB-839 to CPI-613 treatment abrogates the metabolic dependency of HNSCC cells on glutamine, achieving a synergistic anticancer effect in glutamine-addicted HNSCC.
CONCLUSIONS: These findings uncover the critical role of GLS1-mediated glutaminolysis in CPI-613 treatment and suggest that the CB-839 and CPI-613 combination may potentiate synergistic anticancer activity for HNSCC therapeutic gain.

Keywords:  CB-839; CPI-613; Combined targeting; GLS1; Glutaminolysis; HNSCC

DOI:  https://doi.org/10.1186/s13046-021-02207-y
J Neurosci Res. 2021 Dec 13.

Impact of monomeric and aggregated wild-type and A30P/A53T double-mutant α-synuclein on antioxidant mechanism and glutamate metabolic profile of cultured astrocytes.

Aishwarya Raj, Alka Kaushal, Indrani Datta.

  Serving as a source of glutathione and up-taking and metabolizing glutamate are the primary supportive role of astrocytes for the adjacent neurons. Despite the clear physical association between astrocytes and α-synuclein, the effect of extracellular α-synuclein on these astrocytic functions has not yet been elucidated. Hence, we aim to assess the effect of various forms of α-synuclein on antioxidant mechanism and glutamate metabolism. Wild-type and A53T/A30P double-mutant α-synuclein, both in monomeric and aggregated forms, were added extracellularly to media of midbrain rat astrocyte culture, with their survival, oxidative, and nitrative stress, glutathione and glutamate content, expression of enzymes associated with oxidative stress and glutamate metabolism, glutamate and glutathione transporters being assessed along with the association/engulfment of these peptides by astrocytes. A30P/A53T peptide associated more with astrocytes, and low-extracellular K+ concentration showed prominent reduction in the engulfment of the monomeric forms, suggesting that the association of the aggregated forms was greater with the membrane. The peptide-associated astrocytes showed lower survival and increased oxidative stress generation, owing to the decrease in nuclear localization of Nrf2 and increase in iNOS, and further aggravated by the decrease in glutathione content and related enzymes like glutathione synthetase, glutathione peroxidase, and glutathione reductase. Glutamate uptake increased in aggregate-treated cells due to the increase in GLAST1 expression, de novo synthesis of glutamate by pyruvate carboxylase, and/or glutamine synthase, bolstered by the differential glutamate dehydrogenase enzyme activity. We thus show for the first time that extracellular α-synuclein exposure leads to astrocytic dysfunction with respect to the antioxidant mechanism and glutamate metabolic profile. The impact was higher in the case of the aggregated and mutated peptide, with the highest dysfunction for the mutant aggregated α-synuclein treatment.

Keywords:  Nrf2-regulated antioxidants; RRID:SCR_001905; RRID:SCR_002798; RRID:SCR_003070; RRID:SCR_003210; RRID:SCR_013673; astrocytes; extracellular α-synuclein; glutamate uptake and metabolism; glutathione; membrane association/endocytosis

DOI:  https://doi.org/10.1002/jnr.24994
Signal Transduct Target Ther. 2021 Dec 17. 6(1): 421

An RNA-RNA crosstalk network involving HMGB1 and RICTOR facilitates hepatocellular carcinoma tumorigenesis by promoting glutamine metabolism and impedes immunotherapy by PD-L1+ exosomes activity.

Yanping Wei, Xuewu Tang, Yibin Ren, Yun Yang, Fengliang Song, Jingbo Fu, Shuowu Liu, Miao Yu, Jing Chen, Suyang Wang, Kecheng Zhang, Yexiong Tan, Zhipeng Han, Lixin Wei, Baohua Zhang, Zhangjun Cheng, Liang Li, Hongyang Wang.

Hepatocellular carcinoma (HCC) is the global leading cause of cancer-related deaths due to the deficiency of targets for precision therapy. A new modality of epigenetic regulation has emerged involving RNA-RNA crosstalk networks where two or more competing endogenous RNAs (ceRNAs) bind to the same microRNAs. However, the contribution of such mechanisms in HCC has not been well studied. Herein, potential HMGB1-driven RNA-RNA crosstalk networks were evaluated at different HCC stages, identifying the mTORC2 component RICTOR as a potential HMGB1 ceRNA in HBV+ early stage HCC. Indeed, elevated HMGB1 mRNA was found to promote the expression of RICTOR mRNA through competitively binding with the miR-200 family, especially miR-429. Functional assays employing overexpression or interference strategies demonstrated that the HMGB1 and RICTOR 3'untranslated regions (UTR) epigenetically promoted the malignant proliferation, self-renewal, and tumorigenesis in HCC cells. Intriguingly, interference against HMGB1 and RICTOR in HCC cells promoted a stronger anti-PD-L1 immunotherapy response, which appeared to associate with the production of PD-L1+ exosomes. Mechanistically, the HMGB1-driven RNA-RNA crosstalk network facilitated HCC cell glutamine metabolism via dual mechanisms, activating a positive feedback loop involving mTORC2-AKT-C-MYC to upregulate glutamine synthetase (GS) expression, and inducing mTORC1 signaling to derepress SIRT4 on glutamate dehydrogenase (GDH). Meanwhile, this crosstalk network could impede the efficacy of immunotherapy through mTORC1-P70S6K dependent PD-L1 production and PD-L1+ exosomes activity. In conclusion, our study highlights the non-coding regulatory role of HMGB1 with implications for RNA-based therapeutic targeting together with a prediction of anti-PD-L1 immunotherapy in HCC.

DOI: https://doi.org/10.1038/s41392-021-00801-2
Autophagy. 2021 Dec 14. 1-17

ATG12 deficiency results in intracellular glutamine depletion, abrogation of tumor hypoxia and a favorable prognosis in cancer.

Tom G Keulers, Alexander Koch, Marike W van Gisbergen, Lydie M O Barbeau, Marijke I Zonneveld, Monique C de Jong, Kim G M Savelkouls, Roel G Wanders, Johan Bussink, Veerle Melotte, Kasper M A Rouschop.

  Hypoxia is a common feature of solid tumors and is associated with increased tumor progression, resistance to therapy and increased metastasis. Hence, tumor hypoxia is a prognostic factor independent of treatment modality. To survive hypoxia, cells activate macroautophagy/autophagy. Paradoxically, in several cancer types, mutations or loss of essential autophagy genes have been reported that are associated with earlier onset of tumor growth. However, to our knowledge, the phenotypic and therapeutic consequences of autophagy deficiency have remained unexplored. In this study, we determined autophagy-defects in head and neck squamous cell carcinoma (HNSCC) and observed that expression of ATG12 (autophagy related 12) was lost in 25%-40% of HNSCC. In line, ATG12 loss is associated with absence of hypoxia, as determined by pimonidazole immunohistochemistry. Hence, ATG12 loss is associated with improved prognosis after therapy in two independent HNSCC cohorts and 7 additional cancer types. In vivo, ATG12 targeting resulted in decreased hypoxia tolerance, increased necrosis and sensitivity of the tumor to therapy, but in vitro ATG12-deficient cells displayed enhanced survival in nutrient-rich culture medium. Besides oxygen, delivery of glucose was hampered in hypoxic regions in vivo, which increases the reliance of cells on other carbon sources (e.g., L-glutamine). We observed decreased intracellular L-glutamine levels in ATG12-deficient cells during hypoxia and increased cell killing after L-glutamine depletion, indicating a central role for ATG12 in maintaining L-glutamine homeostasis. Our results demonstrate that ATG12low tumors represent a phenotypically different subtype that, due to the lowered hypoxia tolerance, display a favorable outcome after therapy.Abbreviations: ARCON:accelerated radiotherapy with carbogen and nicotinamide; ATG: autophagy related; BrdUrd: bromodeoxyuridine; CA9/CAIX: carbonic anhydrase 9; HIF1A/HIF1α: hypoxia inducible factor 1 subunit alpha; HNSCC: head and neck squamous cell carcinoma; HPV: human papilloma virus; HR: hazard ratio; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; mRNA: messenger ribonucleic acid; PCR: polymerase chain reaction; SLC2A1/GLUT1: solute carrier family 2 member 1; TCGA: the Cancer Genome Atlas; TME: tumor microenvironment; UTR: untranslated region; VEGF: vascular endothelial growth factor.

Keywords:  Autophagy; cancer; glucose; head and neck cancer; hypoxia; prognosis; radiotherapy glutamine

DOI:  https://doi.org/10.1080/15548627.2021.2008690
Behav Brain Res. 2021 Dec 11. pii: S0166-4328(21)00603-3. [Epub ahead of print] 113715

Anorexia disrupts glutamate-glutamine homeostasis associated with astrocytes in the prefrontal cortex of young female rats.

Pamela Reyes-Ortega, María Berenice Soria-Ortiz, Verónica M Rodríguez, Eva Olivia Vázquez-Martínez, Mauricio Díaz-Muñoz, Daniel Reyes-Haro.

  Anorexia nervosa is an eating disorder characterized by self-starvation and excessive weight loss with a notorious prevalence in young women. The neurobiology of AN is unknown but murine models, like dehydration induced anorexia, reproduce weight loss and avoidance of food despite its availability. Astrocytes are known to provide homeostatic support to neurons, but it is little explored if anorexia affects this function. In this study, we tested if DIA disrupts glutamate-glutamine homeostasis associated with astrocytes in the prefrontal cortex of young female rats. Our results showed that anorexia reduced the lactate/pyruvate ratio, as well as endogenous glutamate and glutamine. These effects correlated with a reduced expression of the glutamate transporters (GLT-1 and GLAST) and glutamine synthetase, all of them are preferentially expressed by astrocytes. Accordingly, the expression of GFAP was reduced. Anorexia reduced the astrocyte density, promoted a de-ramified morphology, and augmented the de-ramified/ramified astrocyte ratio in the medial prefrontal cortex and orbitofrontal cortex, but not in the motor cortex (M2). The increase of a de-ramified phenotype correlated with increased expression of vimentin and nestin. Based on these results, we conclude that anorexia disrupts glutamate-glutamine homeostasis and the redox state associated with astrocyte dysfunction.

Keywords:  Anorexia; GFAP; food avoidance; food restriction; glutamate transporters; glutamine synthetase

DOI:  https://doi.org/10.1016/j.bbr.2021.113715
J Biol Chem. 2021 Dec 14. pii: S0021-9258(21)01305-3. [Epub ahead of print] 101495

Oncogenic Gq/11 signaling acutely drives and chronically sustains metabolic reprogramming in uveal melanoma.

Michael D Onken, Sarah E Noda, Kevin M Kaltenbronn, Cheryl Frankfater, Carol M Makepeace, Nikki Fettig, Kisha D Piggott, Philip L Custer, Joseph E Ippolito, Kendall J Blumer.

  Metabolic reprogramming has been shown to occur in uveal melanoma (UM), the most common intraocular tumor in adults. Mechanisms driving metabolic reprogramming in UM are poorly understood. Elucidation of these mechanisms could inform development of new therapeutic strategies for metastatic UM, which has poor prognosis because existing therapies are ineffective. Here, we determined whether metabolic reprogramming is driven by constitutively active mutant α-subunits of the heterotrimeric G proteins Gq or G11 (Gq/11), the oncogenic drivers in ∼90% of UM patients. Using PET-CT imaging, microphysiometry, and gas chromatography/mass spectrometry, we found that inhibition of oncogenic Gq/11 with the small molecule FR900359 (FR) attenuated glucose uptake by UM cells in vivo and in vitro, blunted glycolysis and mitochondrial respiration in UM cell lines and tumor cells isolated from patients, and reduced levels of several glycolytic and TCA cycle intermediates. FR acutely inhibited glycolysis and respiration, and chronically attenuated expression of genes in both metabolic processes. UM therefore differs from other melanomas that exhibit a classic Warburg effect. Metabolic reprogramming in UM cell lines and patient samples involved protein kinase C and Erk1/2 signaling downstream of oncogenic Gq/11. Chronic administration of FR upregulated expression of genes involved in metabolite scavenging and redox homeostasis, potentially as an adaptive mechanism explaining why FR does not efficiently kill UM tumor cells or regress UM tumor xenografts. These results establish that oncogenic Gq/11 signaling is a crucial driver of metabolic reprogramming in UM and lay a foundation for studies aimed at targeting metabolic reprogramming for therapeutic development.

Keywords:  Gq/11; metabolism; oncogenes; signaling; uveal melanoma

DOI:  https://doi.org/10.1016/j.jbc.2021.101495
Cancer Res. 2021 Dec 15. pii: canres.CAN-21-2745-E.2021. [Epub ahead of print]

Integrated Metabolic Profiling and Transcriptional Analysis Reveals Therapeutic Modalities for Targeting Rapidly Proliferating Breast Cancers.

Chengheng Liao, Cherise Ryan Glodowski, Cheng Fan, Juan Liu, Kevin R Mott, Akash Kaushik, Hieu Vu, Jason W Locasale, Samuel K McBrayer, Ralph J DeBerardinis, Charles M Perou, Qing Zhang.

Metabolic dysregulation is a prominent feature in breast cancer, but it remains poorly characterized in patient tumors. In this study, untargeted metabolomics analysis of triple-negative breast cancer (TNBC) and estrogen receptor (ER)-positive breast cancer patient samples, as well as TNBC patient-derived xenografts (PDX), revealed two major metabolic groups independent of breast cancer histological subtypes: a "Nucleotide/Carbohydrate-Enriched" group and a "Lipid/Fatty Acid-Enriched" group. Cell lines grown in vivo more faithfully recapitulated the metabolic profiles of patient tumors compared to those grown in vitro. Integrated metabolic and gene expression analyses identified genes that strongly correlate with metabolic dysregulation and predict patient prognosis. As a proof-of-principle, targeting Nucleotide/Carbohydrate-Enriched TNBC cell lines or PDX xenografts with a pyrimidine biosynthesis inhibitor or a glutaminase inhibitor led to therapeutic efficacy. In multiple in vivo models of TNBC, treatment with the pyrimidine biosynthesis inhibitor conferred better therapeutic outcomes than chemotherapeutic agents. This study provides a metabolic stratification of breast tumor samples that can guide the selection of effective therapeutic strategies targeting breast cancer subsets. In addition, we have developed a public, interactive data visualization portal (http://brcametab.org) based on the data generated from this study to facilitate future research.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-2745
Front Mol Biosci. 2021 ;8 763902

Recent Metabolomics Analysis in Tumor Metabolism Reprogramming.

Jingjing Han, Qian Li, Yu Chen, Yonglin Yang.

  Metabolic reprogramming has been suggested as a hallmark of cancer progression. Metabolomic analysis of various metabolic profiles represents a powerful and technically feasible method to monitor dynamic changes in tumor metabolism and response to treatment over the course of the disease. To date, numerous original studies have highlighted the application of metabolomics to various aspects of tumor metabolic reprogramming research. In this review, we summarize how metabolomics techniques can help understand the effects that changes in the metabolic profile of the tumor microenvironment on the three major metabolic pathways of tumors. Various non-invasive biofluids are available that produce accurate and useful clinical information on tumor metabolism to identify early biomarkers of tumor development. Similarly, metabolomics can predict individual metabolic differences in response to tumor drugs, assess drug efficacy, and monitor drug resistance. On this basis, we also discuss the application of stable isotope tracer technology as a method for the study of tumor metabolism, which enables the tracking of metabolite activity in the body and deep metabolic pathways. We summarize the multifaceted application of metabolomics in cancer metabolic reprogramming to reveal its important role in cancer development and treatment.

Keywords:  biomarkers; drug resistance; metabolic reprogramming; metabolomics; stable isotope resolved metabolomics

DOI:  https://doi.org/10.3389/fmolb.2021.763902
Biomed Pharmacother. 2021 Dec 11. pii: S0753-3322(21)01313-5. [Epub ahead of print]146 112526

Cell line-directed breast cancer research based on glucose metabolism status.

Pegah Farhadi, Reza Yarani, Elahe Valipour, Sarah Kiani, Zohreh Hoseinkhani, Kamran Mansouri.

  Metabolic reprogramming is a potential hallmark of tumor cells to support continuous proliferation. Metabolic heterogeneity in breast cancer patients has been highlighted as the driving cause of tumor progression and resistance to anticancer drugs. Studying and identifying distinct metabolic alterations in breast cancer subtypes could offer new perspectives for faster diagnosis and treatment. Given cancer cell dependency on glycolysis, the primary energy source, this enzymatic pathway will play a critical role in targeting therapies. Knowledge about the specific metabolic dependencies of tumors for growth and proliferation can be promising for novel targeted and cell-based therapies. Here, the metabolic status with emphasis on glycolysis of breast cancer cell lines according to their classification was reviewed.

Keywords:  Breast cancer cell lines; Glycolysis; Metabolism status; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.biopha.2021.112526
Clin Exp Metastasis. 2021 Dec 18.

Defining the landscape of metabolic dysregulations in cancer metastasis.

Sara Abdul Kader, Shaima Dib, Iman W Achkar, Gaurav Thareja, Karsten Suhre, Arash Rafii, Anna Halama.

  Metastasis is the primary cause of cancer related deaths due to the limited number of efficient druggable targets. Signatures of dysregulated cancer metabolism could serve as a roadmap for the determination of new treatment strategies. However, the metabolic signatures of metastatic cells remain vastly elusive. Our aim was to determine metabolic dysregulations associated with high metastatic potential in breast cancer cell lines. We have selected 5 triple negative breast cancer (TNBC) cell lines including three with high metastatic potential (HMP) (MDA-MB-231, MDA-MB-436, MDA-MB-468) and two with low metastatic potential (LMP) (BT549, HCC1143). The normal epithelial breast cell line (hTERT-HME1) was also investigated. The untargeted metabolic profiling of cells and growth media was conducted and total of 479 metabolites were quantified. First we characterized metabolic features differentiating TNBC cell lines from normal cells as well as identified cell line specific metabolic fingerprints. Next, we determined 92 metabolites in cells and 22 in growth medium that display significant differences between LMP and HMP. The HMP cell lines had elevated level of molecules involved in glycolysis, TCA cycle and lipid metabolism. We identified metabolic advantages of cell lines with HMP beyond enhanced glycolysis by pinpointing the role of branched chain amino acids (BCAA) catabolism as well as molecules supporting coagulation and platelet activation as important contributors to the metastatic cascade. The landscape of metabolic dysregulations, characterized in our study, could serve as a roadmap for the identification of treatment strategies targeting cancer cells with enhanced metastatic potential.

Keywords:  Branch chain amino acid metabolism; Metabolic profiling; Metastasis; Metastatic potential; TCA cycle; Triple negative breast cancer

DOI:  https://doi.org/10.1007/s10585-021-10140-9
Protein Cell. 2021 Dec 16.

Governing glutaminolysis by regulation of glutaminase succinylation.

Qingxia Ma, Hongfei Jiang, Leina Ma, Ying Meng, Dong Guo, Yingying Tong, Zhimin Lu.

DOI: https://doi.org/10.1007/s13238-021-00897-w
Drug Metab Lett. 2021 Dec 09.

Physiological and Pathophysiological Role of Cysteine Metabolism in Human Metabolic Syndrome.

Arunachalam Muthuraman, Muthusamy Ramesh, Sohrab A Shaikh, Subramanian Aswinprakash, Dhamodharan Jagadeesh.

  Cysteine is one of the major intermediate products of cellular amino-acid metabolism. It is a semi-essential amino acid for protein synthesis. Besides, it is also employed in the regulation of major endogenous anti-oxidant molecules i.e., reduced glutathione (GSH). Further, it is a precursor of multiple sulfur-containing molecules like hydrogen sulfide, lanthionine, taurine, coenzyme A and biotin. It is also one of the key molecules for post-translational modifications of various cellular proteins. In physiological conditions, it is employed in the sulfhydration process and plays a key role in the physiology modification of the inflammatory process in various organs, including the neurological system. The catabolism of cysteine is regulated by cysteine dioxygenase enzyme activity. The dysregulated conditions of cysteine and cysteine-associated hydrogen sulfide metabolism are widely employed in the acceleration of the neurodegenerative process. Moreover, the upregulation of cysteine and hydrogen sulfide synthesis occurs via the reverse trans-sulfuration process. This process helps to manage the worsening of a pathological condition of a cellular system. Moreover, it is also employed in the accumulation of homocysteine contents. Further, both cysteine and homocysteine molecules are widely accepted as biomarkers for various types of diseases. Therefore, the targets involved in the regulation of cysteine have been considered as valid targets to treat various disorders like cardiac disease, ischemic stroke, diabetes, cancer, and renal dysfunction.

Keywords:  Biomarker; homocysteine; hydrogen sulfide; reduced glutathione; stroke

DOI:  https://doi.org/10.2174/1872312814666211210111820
Cancer Metastasis Rev. 2021 Dec 16.

Tumor metabolism: metabolic alterations and heterogeneity in cancer progression.

Anna Sebestyén.

DOI: https://doi.org/10.1007/s10555-021-10008-0