bims-glucam 2021-07-11 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021‒07‒11
twelve papers selected by
Sreeparna Banerjee
Middle East Technical University

Hepatoblastoma: glutamine depletion hinders cell viability in the embryonal subtype but high GLUL expression is associated with better overall survival.
The expression of miR-513c and miR-3163 was downregulated in tumor tissues compared with normal adjacent tissue of patients with breast cancer.
Local production of lactate, ribose phosphate, and amino acids within human triple-negative breast cancer.
Glutamine for prevention and alleviation of radiation-induced oral mucositis in patients with head and neck squamous cell cancer: A systematic review and meta-analysis of controlled trials.
Metabolic Enzyme DLST Promotes Tumor Aggression and Reveals a Vulnerability to OXPHOS Inhibition in High-Risk Neuroblastoma.
ONC212 is a novel mitocan acting synergistically with glycolysis inhibition in pancreatic cancer.
The therapeutic implications of immunosuppressive tumor aerobic glycolysis.
Metabolic reprogramming in cancer: mechanistic insights from Drosophila.
Monitoring of circulating amino acids in patients with pancreatic cancer and cancer cachexia using capillary electrophoresis and contactless conductivity detection.
Oncogenic KRAS creates an aspartate metabolism signature in colorectal cancer cells.
Enzymatic activation of pyruvate kinase increases cytosolic oxaloacetate to inhibit the Warburg effect.
SIRT5 Is a Druggable Metabolic Vulnerability in Acute Myeloid Leukemia.

J Cancer Res Clin Oncol. 2021 Jul 07.

Hepatoblastoma: glutamine depletion hinders cell viability in the embryonal subtype but high GLUL expression is associated with better overall survival.

Andreas Schmidt, Angela Armento, Ovidio Bussolati, Martina Chiu, Verena Ellerkamp, Marcus O Scharpf, Philip Sander, Evi Schmid, Steven W Warmann, Jörg Fuchs.

  PURPOSE: Glutamine plays an important role in cell viability and growth of various tumors. For the fetal subtype of hepatoblastoma, growth inhibition through glutamine depletion was shown. We studied glutamine depletion in embryonal cell lines of hepatoblastoma carrying different mutations. Since asparagine synthetase was identified as a prognostic factor and potential therapeutic target in adult hepatocellular carcinoma, we investigated the expression of its gene ASNS and of the gene GLUL, encoding for glutamine synthetase, in hepatoblastoma specimens and cell lines and investigated the correlation with overall survival.METHODS: We correlated GLUL and ASNS expression with overall survival using publicly available microarray and clinical data. We examined GLUL and ASNS expression by RT-qPCR and by Western blot analysis in the embryonal cell lines Huh-6 and HepT1, and in five hepatoblastoma specimens. In the same cell lines, we investigated the effects of glutamine depletion. Hepatoblastoma biopsies were examined for histology and CTNNB1 mutations.
RESULTS: High GLUL expression was associated with a higher median survival time. Independent of mutations and histology, hepatoblastoma samples showed strong GLUL expression and glutamine synthesis. Glutamine depletion resulted in the inhibition of proliferation and of cell viability in both embryonal hepatoblastoma cell lines. ASNS expression did not correlate with overall survival.
CONCLUSION: Growth inhibition resulting from glutamine depletion, as described for the hepatoblastoma fetal subtype, is also detected in established embryonal hepatoblastoma cell lines carrying different mutations. At variance with adult hepatocellular carcinoma, in hepatoblastoma asparagine synthetase has no prognostic significance.

Keywords:  Asparaginase; Asparagine synthetase; Glutamine depletion; Glutamine synthetase; Hepatoblastoma; Hepatocellular carcinoma

DOI:  https://doi.org/10.1007/s00432-021-03713-4
BMC Med Genomics. 2021 Jul 07. 14(1): 180

The expression of miR-513c and miR-3163 was downregulated in tumor tissues compared with normal adjacent tissue of patients with breast cancer.

Soheila Delgir, Khandan Ilkhani, Asma Safi, Yazdan Rahmati, Vahid Montazari, Zahra Zaynali-Khasraghi, Farhad Seif, Milad Bastami, Mohammad Reza Alivand.

  BACKGROUND: Breast cancer (BC) is the most invasive cancer with different subtypes that its metabolism is unique compared with normal cells. Glutamine is considered critical nutrition that many cancer cells, particularly BC cells, are dependent on it for growth and proliferation. Therefore, targeting glutamine metabolism, especially enzymes that are related to this pathway, can be beneficial to design anti-cancer agents. Recent evidence has shown that microRNAs (miRNAs), with a short length and single-strand properties, play a prominent role in regulating the genes related to glutamine metabolism, which may control the development of cancer.METHODS: In silico analysis confirmed that miR-513c and miR-3163 might be involved in glutamine metabolism. The expression level of these two miRNAs was evaluated in eighty BC tissues and normal adjacent tissues. Furthermore, GSE38167, GSE38867, GSE42128, GSE45666, and GSE53179 were employed from gene expression omnibus (GEO). The Limma package was utilized to identify differentially expressed miRNAs (DEMs) of mentioned datasets to evaluate miR-513c and miR-3163 expression. Further, in silico analysis was utilized to predict the potential biological processes and molecular pathways of miR-513c and miR-3163, based on their target genes.
RESULTS: In silico studies revealed top categories of biological processes and cellular pathways that might play a critical role in metabolism reprogramming and cancer development and were target genes for miR-513c and miR-3163. The current study showed that miR-513c (p value = 0.02062 and FC = - 2.3801) and miR-3163 (p value = 0.02034 and FC = - 2.3792) were downregulated in tumor tissues compared to normal adjacent tissues. The analysis of GEO microarray datasets showed that miR-513c was downregulated in GSE38167, GSE38867, GSE42128, GSE45666 and GSE53179, whereas there was a significant downregulation of miR-3163 in only two studies, including GSE38867 and GSE42128 that they were in accordance with our experimental results. Furthermore, the subgroup analysis did not show any substantial relationship between expression levels of these two miRNAs and factors such as age, family history of cancer, and abortion history.
CONCLUSION: MiR-513c and miR-3163 were downregulated in BC tissues, which might serve as tumor suppressors. They are suggested as potential therapeutic targets for patients with BC.

Keywords:  Breast cancer; Fold change; Glutaminase; Glutamine metabolism; MicroRNA; miR-3163; miR-513c

DOI:  https://doi.org/10.1186/s12920-021-01029-3
Med (N Y). 2021 Jun 11. 2(6): 736-754

Local production of lactate, ribose phosphate, and amino acids within human triple-negative breast cancer.

Jonathan M Ghergurovich, Jessica D Lang, Maren K Levin, Natalia Briones, Salvatore J Facista, Claudius Mueller, Alexis J Cowan, Matthew J McBride, Esther San Roman Rodriguez, Aaron Killian, Tuoc Dao, Jeffrey Lamont, Alison Barron, Xiaoyang Su, William P D Hendricks, Virginia Espina, Daniel D Von Hoff, Joyce O'Shaughnessy, Joshua D Rabinowitz.

Background: Upregulated glucose metabolism is a common feature of tumors. Glucose can be broken down by either glycolysis or the oxidative pentose phosphate pathway (oxPPP). The relative usage within tumors of these catabolic pathways remains unclear. Similarly, the extent to which tumors make biomass precursors from glucose, versus take them up from the circulation, is incompletely defined.Methods: We explore human triple negative breast cancer (TNBC) metabolism by isotope tracing with [1,2-13C]glucose, a tracer that differentiates glycolytic versus oxPPP catabolism and reveals glucose-driven anabolism. Patients enrolled in clinical trial NCT03457779 and received IV infusion of [1,2-13C]glucose during core biopsy of their primary TNBC. Tumor samples were analyzed for metabolite labeling by liquid chromatography-mass spectrometry (LC-MS). Genomic and proteomic analyses were performed and related to observed metabolic fluxes.
Findings: TNBC ferments glucose to lactate, with glycolysis dominant over the oxPPP. Most ribose phosphate is nevertheless produced by oxPPP. Glucose also feeds amino acid synthesis, including of serine, glycine, aspartate, glutamate, proline and glutamine (but not asparagine). Downstream in glycolysis, tumor pyruvate and lactate labeling exceeds that found in serum, indicating that lactate exchange via monocarboxylic transporters is less prevalent in human TNBC compared with most normal tissues or non-small cell lung cancer.
Conclusions: Glucose directly feeds ribose phosphate, amino acid synthesis, lactate, and the TCA cycle locally within human breast tumors.

DOI: https://doi.org/10.1016/j.medj.2021.03.009
Head Neck. 2021 Jul 09.

Glutamine for prevention and alleviation of radiation-induced oral mucositis in patients with head and neck squamous cell cancer: A systematic review and meta-analysis of controlled trials.

Hemail M Alsubaie, Albaraa Y Alsini, Khaled M Alsubaie, Ahmed Abu-Zaid, Faisal R Alzahrani, Suhail Sayed, Alok K Pathak, Khaled H Alqahtani.

  We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that investigated glutamine efficacy in preventing and alleviating radiation-induced oral mucositis (OM) among patients with head and neck (H&N) cancer. We screened five databases from inception till February 4, 2021 and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We included 11 RCTs, comprising 922 patients (458 and 464 patients were assigned to glutamine and control group, respectively). The incidence and onset of radiation-induced OM of any grade did not substantially differ between both groups. However, glutamine substantially reduced the severity of radiation-induced OM, as reflected by the reduced incidence of severe OM and reduced mean maximal OM grade score. Additionally, glutamine significantly decreased the rates of analgesic opioid use, nasogastric tube feeding, and therapy interruptions. Oral glutamine supplementation demonstrated various therapeutic benefits in preventing and ameliorating radiation-induced OM among patients with H&N cancer.

Keywords:  chemoradiotherapy; glutamine; head and neck cancer; oral mucositis; radiotherapy

DOI:  https://doi.org/10.1002/hed.26798
Cancer Res. 2021 Jul 07. pii: canres.2153.2020. [Epub ahead of print]

Metabolic Enzyme DLST Promotes Tumor Aggression and Reveals a Vulnerability to OXPHOS Inhibition in High-Risk Neuroblastoma.

Nicole M Anderson, Xiaodan Qin, Jennifer M Finan, Andrew Lam, Jacob Athoe, Rindert Missiaen, Nicolas Skuli, Annie Kennedy, Amandeep S Saini, Ting Tao, Shizhen Zhu, Itzhak Nissim, A Thomas Look, Guoliang Qing, M Celeste Simon, Hui Feng.

High-risk neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood. Here we show that elevated expression of dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in neuroblastoma patients. DLST is an E2 component of the a-ketoglutarate (a-KG) dehydrogenase complex, which governs the entry of glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. During this irreversible step, a-KG is converted into succinyl-CoA, producing NADH for oxidative phosphorylation (OXPHOS). Utilizing a zebrafish model of MYCN-driven neuroblastoma, we demonstrate that even modest increases in DLST expression promote tumor aggression, while monoallelic dlst loss impedes disease initiation and progression. DLST depletion in human MYCN-amplified neuroblastoma cells minimally affected glutamine anaplerosis and did not alter TCA cycle metabolites other than a-KG. However, DLST loss significantly suppressed NADH production and impaired OXPHOS, leading to growth arrest and apoptosis of neuroblastoma cells. Additionally, multiple inhibitors targeting the electron transport chain, including the potent IACS-010759 that is currently in clinical testing for other cancers, efficiently reduced neuroblastoma proliferation in vitro. IACS-010759 also suppressed tumor growth in zebrafish and mouse xenograft models of high-risk neuroblastoma. Together, these results demonstrate that DLST promotes neuroblastoma aggression and unveils OXPHOS as an essential contributor to high-risk neuroblastoma.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-2153
Mol Cancer Ther. 2021 Jun 17. pii: molcanther.MCT-20-0962-A.2020. [Epub ahead of print]

ONC212 is a novel mitocan acting synergistically with glycolysis inhibition in pancreatic cancer.

Isacco Ferrarini, Anna Louie, Lanlan Zhou, Wafik S El-Deiry.

ONC212 is a fluorinated-imipridone with preclinical efficacy against pancreatic and other malignancies. Although mitochondrial protease ClpP was identified as an ONC212-binding target, the mechanism leading to cancer cell death is incompletely understood. We investigated mitochondrial dysfunction and metabolic rewiring triggered by ONC212 in pancreatic cancer, a deadly malignancy with an urgent need for novel therapeutics. We found ClpP is expressed in pancreatic cancer cells and is required for ONC212 cytotoxicity. ClpX, the regulatory binding-partner of ClpP, is suppressed upon ONC212 treatment. Immunoblotting and extracellular flux analysis showed ONC212 impairs oxidative phosphorylation (OXPHOS) with decrease in mitochondrial-derived ATP production. Although collapse of mitochondrial function is observed across ONC212-treated cell lines, only OXPHOS-dependent cells undergo apoptosis. Cells relying on glycolysis undergo growth-arrest and upregulate glucose catabolism to prevent ERK1/2 inhibition and apoptosis. Glucose restriction or combination with glycolytic inhibitor 2-deoxy-D-glucose synergize with ONC212 and promote apoptosis in vitro and in vivo. Thus, ONC212 is a novel mitocan targeting oxidative-metabolism in pancreatic cancer, leading to different cellular outcomes based on divergent metabolic programs.

DOI: https://doi.org/10.1158/1535-7163.MCT-20-0962
Cell Mol Immunol. 2021 Jul 08.

The therapeutic implications of immunosuppressive tumor aerobic glycolysis.

Bradley I Reinfeld, W Kimryn Rathmell, Tae Kon Kim, Jeffrey C Rathmell.

  In 2011, Hanahan and Weinberg added "Deregulating Cellular Energetics" and "Avoiding Immune Destruction" to the six previous hallmarks of cancer. Since this seminal paper, there has been a growing consensus that these new hallmarks are not mutually exclusive but rather interdependent. The following review summarizes how founding genetic events for tumorigenesis ultimately increase tumor cell glycolysis, which not only supports the metabolic demands of malignancy but also provides an immunoprotective niche, promoting malignant cell proliferation, maintenance and progression. The mechanisms by which altered metabolism contributes to immune impairment are multifactorial: (1) the metabolic demands of proliferating tumor cells and activated immune cells are similar, thus creating a situation where immune cells may be in competition for key nutrients; (2) the metabolic byproducts of aerobic glycolysis directly inhibit antitumor immunity while promoting a regulatory immune phenotype; and (3) the gene programs associated with the upregulation of glycolysis also result in the generation of immunosuppressive cytokines and metabolites. From this perspective, we shed light on important considerations for the development of new classes of agents targeting cancer metabolism. These types of therapies can impair tumor growth but also pose a significant risk of stifling antitumor immunity.

Keywords:  cancer; glycolysis; immunology; metabolism

DOI:  https://doi.org/10.1038/s41423-021-00727-3
Dis Model Mech. 2021 Jul 01. 14(7): 1-17

Metabolic reprogramming in cancer: mechanistic insights from Drosophila.

Kenneth Kin Lam Wong, Esther M Verheyen.

  Cancer cells constantly reprogram their metabolism as the disease progresses. However, our understanding of the metabolic complexity of cancer remains incomplete. Extensive research in the fruit fly Drosophila has established numerous tumor models ranging from hyperplasia to neoplasia. These fly tumor models exhibit a broad range of metabolic profiles and varying nutrient sensitivity. Genetic studies show that fly tumors can use various alternative strategies, such as feedback circuits and nutrient-sensing machinery, to acquire and consolidate distinct metabolic profiles. These studies not only provide fresh insights into the causes and functional relevance of metabolic reprogramming but also identify metabolic vulnerabilities as potential targets for cancer therapy. Here, we review the conceptual advances in cancer metabolism derived from comparing and contrasting the metabolic profiles of fly tumor models, with a particular focus on the Warburg effect, mitochondrial metabolism, and the links between diet and cancer.

Keywords:   Drosophila cancer models; Aerobic glycolysis; Metabolic reprogramming; Mitochondria

DOI:  https://doi.org/10.1242/dmm.048934
Electrophoresis. 2021 Jul 06.

Monitoring of circulating amino acids in patients with pancreatic cancer and cancer cachexia using capillary electrophoresis and contactless conductivity detection.

Petr Tůma, Tomáš Hložek, Jana Kamišová, Jan Gojda.

  Branched chain amino acids (BCAAs), alanine and glutamine are determined in human plasma by capillary electrophoresis with contactless conductivity detection (CE/C4 D). The baseline separation of five amino acids from other plasma components is achieved on the short capillary effective length of 18 cm in 3.2 mol/L acetic acid with addition of 13% v/v methanol as background electrolyte. Migration times range from 2.01 min for valine to 2.84 min for glutamine, and LODs for untreated plasma are in the interval 0.7-0.9 μmol/L. Sample treatment is based on the addition of acetonitrile to only 15 μL of plasma and supernatant is directly subjected to CE/C4 D. Circulating amino acids are measured in patients with pancreatic cancer and cancer cachexia during oral glucose tolerance test. It is shown that patients with pancreatic cancer and cancer cachexia syndrome exhibit low basal circulating BCAAs and glutamine levels and loss of their insulin-dependent suppression. This article is protected by copyright. All rights reserved.

Keywords:  Branched chain amino acids; Cancer cachexia; Capillary electrophoresis; Contactless conductivity detection; Insulin

DOI:  https://doi.org/10.1002/elps.202100174
FEBS J. 2021 Jul 06.

Oncogenic KRAS creates an aspartate metabolism signature in colorectal cancer cells.

Peter F Doubleday, Luca Fornelli, Ioanna Ntai, Neil L Kelleher.

  Oncogenic mutations in the KRAS gene are found in 30-50% of colorectal cancers (CRC) and recent findings have demonstrated independent and non-redundant roles for wild-type and mutant KRAS alleles in governing signaling and metabolism. Here, we quantify proteomic changes manifested by KRAS mutation and KRAS allele loss in isogenic cell lines. We show that expression of KRASG13D upregulates aspartate metabolizing proteins including PCK1, PCK2, ASNS and ASS1. Furthermore, differential expression analyses of transcript-level data from CRC tumors identified the upregulation of urea cycle enzymes in CRC. We find that expression of ASS1, supports colorectal cancer cell proliferation and promotes tumor formation in vitro. We show that loss of ASS1 can be rescued with high levels of several metabolites.

Keywords:  Quantitative proteomics; aspartate; colorectal cancer; metabolomics; mutant KRAS; urea cycle

DOI:  https://doi.org/10.1111/febs.16111
Nat Metab. 2021 Jul 05.

Enzymatic activation of pyruvate kinase increases cytosolic oxaloacetate to inhibit the Warburg effect.

Elizabeth K Wiese, Sadae Hitosugi, Sharon T Loa, Annapoorna Sreedhar, Lindsey G Andres-Beck, Kiran Kurmi, Yuan-Ping Pang, Larry M Karnitz, Wilson I Gonsalves, Taro Hitosugi.

Pharmacological activation of the glycolytic enzyme PKM2 or expression of the constitutively active PKM1 isoform in cancer cells results in decreased lactate production, a phenomenon known as the PKM2 paradox in the Warburg effect. Here we show that oxaloacetate (OAA) is a competitive inhibitor of human lactate dehydrogenase A (LDHA) and that elevated PKM2 activity increases de novo synthesis of OAA through glutaminolysis, thereby inhibiting LDHA in cancer cells. We also show that replacement of human LDHA with rabbit LDHA, which is relatively resistant to OAA inhibition, eliminated the paradoxical correlation between the elevated PKM2 activity and the decreased lactate concentration in cancer cells treated with a PKM2 activator. Furthermore, rabbit LDHA-expressing tumours, compared to human LDHA-expressing tumours in mice, displayed resistance to the PKM2 activator. These findings describe a mechanistic explanation for the PKM2 paradox by showing that OAA accumulates and inhibits LDHA following PKM2 activation.

DOI: https://doi.org/10.1038/s42255-021-00424-5
Cancer Discov. 2021 May;2(3): 266-287

SIRT5 Is a Druggable Metabolic Vulnerability in Acute Myeloid Leukemia.

Dongqing Yan, Anca Franzini, Anthony D Pomicter, Brayden J Halverson, Orlando Antelope, Clinton C Mason, Jonathan M Ahmann, Anna V Senina, Nadeem A Vellore, Courtney L Jones, Matthew S Zabriskie, Hein Than, Michael J Xiao, Alexandria van Scoyk, Ami B Patel, Phillip M Clair, William L Heaton, Shawn C Owen, Joshua L Andersen, Christina M Egbert, Julie A Reisz, Angelo D'Alessandro, James E Cox, Kevin C Gantz, Hannah M Redwine, Siddharth M Iyer, Jamshid S Khorashad, Nima Rajabi, Christian A Olsen, Thomas O'Hare, Michael W Deininger.

We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML. SIGNIFICANCE: Reducing SIRT5 activity is detrimental to the survival of AML cells regardless of genotype, yet well tolerated by healthy hematopoietic cells. In mouse models, disrupting SIRT5 inhibits AML progression. SIRT5 controls several metabolic pathways that are required for leukemia cell survival. These results identify SIRT5 as a therapeutic target in AML.See related commentary by Li and Melnick, p. 198.

DOI: https://doi.org/10.1158/2643-3230.BCD-20-0168