bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2020–10–25
six papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Glutaminase inhibitors induce thiol-mediated oxidative stress and radio-sensitization in treatment resistant cervical cancers.
  2. Antitumorigenic Effect of Memantine via Interfering Glutamate Metabolism in Mouse 4T1 Breast Tumor Model.
  3. Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1.
  4. Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer.
  5. Glutamine Deficiency Links Clindamycin-Induced Dysbiosis and Intestinal Barrier Dysfunction in Mice.
  6. Azithromycin resistance mutations in Streptococcus pneumoniae as revealed by a chemogenomic screen.
  1. Mol Cancer Ther. 2020 Oct 21. pii: molcanther.0271.2020. [Epub ahead of print]
    Glutaminase inhibitors induce thiol-mediated oxidative stress and radio-sensitization in treatment resistant cervical cancers.
    Ramachandran Rashmi, Kay Jayachandran, Jin Zhang, Vishnu Menon, Naoshad Muhammad, Michael Zahner, Fiona Ruiz, Sisi Zhang, Kevin Cho, Yuting Wang, Xiaojing Huang, Yi Huang, Michael L McCormick, Buck E Rogers, Douglas R Spitz, Gary J Patti, Julie K Schwarz.
      The purpose of the study was to determine if radiation resistant cervical cancers are dependent upon glutamine metabolism driven by activation of the PI3K pathway and test whether PI3K pathway mutation predicts radio-sensitization by inhibition of glutamine metabolism. Cervical cancer cell lines with and without PI3K pathway mutations, including SiHa and SiHa PTEN-/- cells engineered by CRISPR/Cas9, were used for mechanistic studies performed in vitro in the presence and absence of glutamine starvation and the glutaminase inhibitor, telaglenastat (CB-839). These studies included cell survival, proliferation, quantification of oxidative stress parameters, metabolic tracing with stable isotope labeled substrates, metabolic rescue and combination studies with L-buthionine sulfoximine (BSO), auranofin (AUR), and radiation (RT). In vivo studies of telaglenastat ± RT were performed using CaSki and SiHa xenografts grown in immune compromised mice. PI3K activated cervical cancer cells were selectively sensitive to glutamine deprivation through a mechanism that included thiol-mediated oxidative stress. Telaglenastat treatment decreased total glutathione pools, increased the percent glutathione disulfide, and caused clonogenic cell killing that was reversed by treatment with the thiol antioxidant, N-acetylcysteine. Telaglenastat also sensitized cells to killing by glutathione depletion with BSO, thioredoxin reductase inhibition with AUR, and RT. Glutamine dependent PI3K activated cervical cancer xenografts were sensitive to telaglenastat monotherapy, and telaglenastat selectively radio-sensitized cervical cancer cells in vitro and in vivo. These novel preclinical data support the utility of telaglenastat for glutamine dependent radio-resistant cervical cancers and demonstrate that PI3K pathway mutations may be used as a predictive biomarker for telaglenastat sensitivity.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-20-0271
  2. Anticancer Agents Med Chem. 2020 Oct 20.
    Antitumorigenic Effect of Memantine via Interfering Glutamate Metabolism in Mouse 4T1 Breast Tumor Model.
    Gulsah Albayrak, Funda D Korkmaz, Elif B Bali, Emin U Bagriacik.
       BACKGROUND: Repurposing drugs is an efficient strategy as drug discovery process is time-consuming, laborious and costly. Memantine is already used in Alzheimer's disease to prevent neurons from excess glutamate toxicity. As cancer cells benefit higher amounts of cellular energetics like glucose and glutamine, we used memantine to interfere with the glutamate metabolism in order to restrict cancer cells glutamine as a source for their growth.
    OBJECTIVE: To investigate the potential antitumor effect of memantine by reducing glutamate levels in 4T1 mouse breast cancer model.
    METHODS: 24 Balb/c female mice were subcutaneously inoculated with 4T1 cells. When tumors were palpable memantine treatment was initiated as 5 and 10 mg/kg daily intraperitoneal injection. Tumor growth was recorded for every 2-3 days. Tumor volumes, serum glutamate levels, spleen IL-6 levels, genome-wide DNA methylation levels and GSK3B. pGSK3B protein expressions were measured to enlighten the anticancer mechanism of action for memantine.
    RESULTS: We found that both two doses (5 and 10mg/kg) decreased tumor growth rates and serum glutamate levels significantly (p<0.05). 10mg/kg treatment increased spleen IL-6 levels (p<0.05) and decreased genome-wide DNA methylation levels. Memantine treatment decreased GSK3B protein expression levels in tumor tissue samples.
    CONCLUSION: To the best of our knowledge this is the first study that investigates the antitumor activity of memantine in breast cancer tumor model. Our results suggest a potent anticancer mechanism of action for memantine. Memantine decreased genome wide methylation and serum glutamate levels that are associated with a poor prognosis. Therefore, Memantine might be used for targeting glutamine metabolism in cancer treatment.
    Keywords:  4T1; antitumorigenic effect; cancer; glutamate metabolism; in vivo; memantine
    DOI:  https://doi.org/10.2174/0929867327666201020155733
  3. J Clin Med. 2020 Oct 15. pii: E3308. [Epub ahead of print]9(10):
    Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1.
    Céline A Schoonjans, Barbara Mathieu, Nicolas Joudiou, Luca X Zampieri, Davide Brusa, Pierre Sonveaux, Olivier Feron, Bernard Gallez.
      Targeting endothelial cell (EC) metabolism should impair angiogenesis, regardless of how many angiogenic signals are present. The dependency of proliferating ECs on glucose and glutamine for energy and biomass production opens new opportunities for anti-angiogenic therapy in cancer. The aim of the present study was to investigate the role of pyruvate dehydrogenase kinase (PDK) inhibition with dichloroacetate (DCA), alone or in combination with the glutaminase-1 (GLS-1) inhibitor, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES), on Human umbilical vein endothelial cells (HUVECs) metabolism, proliferation, apoptosis, migration, and vessel formation. We demonstrated that both drugs normalize HUVECs metabolism by decreasing glycolysis for DCA and by reducing glutamate production for BPTES. DCA and BPTES reduced HUVECs proliferation and migration but have no impact on tube formation. While DCA increased HUVECs respiration, BPTES decreased it. Using both drugs in combination further reduced HUVECs proliferation while normalizing respiration and apoptosis induction. Overall, we demonstrated that DCA, a metabolic drug under study to target cancer cells metabolism, also affects tumor angiogenesis. Combining DCA and BPTES may reduce adverse effect of each drug alone and favor tumor angiogenesis normalization.
    Keywords:  13C-NMR; BPTES; dichloroacetate; endothelial cells metabolism; glutaminolysis inhibition; glycolysis inhibition; tumor microenvironment
    DOI:  https://doi.org/10.3390/jcm9103308
  4. Cancers (Basel). 2020 Oct 17. pii: E3023. [Epub ahead of print]12(10):
    Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer.
    Janine M DeBlasi, Gina M DeNicola.
      The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting evidence now implicates the ability of NRF2 to modulate metabolic processes, particularly those at the interface between antioxidant processes and cellular proliferation. Notably, NRF2 regulates the pentose phosphate pathway, NADPH production, glutaminolysis, lipid and amino acid metabolism, many of which are hijacked by cancer cells to promote proliferation and survival. Moreover, deregulation of metabolic processes in both normal and cancer-based physiology can stabilize NRF2. We will discuss how perturbation of metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and autophagy can lead to NRF2 stabilization, and how NRF2-regulated metabolism helps cells deal with these metabolic stresses. Finally, we will discuss how the negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), may play a role in metabolism through NRF2 transcription-independent mechanisms. Collectively, this review will address the interplay between the NRF2/KEAP1 complex and metabolic processes.
    Keywords:  KEAP1; NADPH; NRF2; amino acids; cancer metabolism; lipids; oxidative stress
    DOI:  https://doi.org/10.3390/cancers12103023
  5. Br J Nutr. 2020 Oct 22. 1-23
    Glutamine Deficiency Links Clindamycin-Induced Dysbiosis and Intestinal Barrier Dysfunction in Mice.
    Jinyan Mao, Yongheng Yan, Hongling Li, Xudan Shen, Hao Zhang, Haitao Li, Wei Chen.
      Antibiotic rank the most powerful weapons against bacterial infection, but their use is often limited by antibiotic-associated diarrhea (AAD). Here we reported that glutamine deficiency might act as a new link between clindamycin-induced dysbiosis and intestinal barrier dysfunction during AAD progression. Using a mouse model, we demonstrated that glutamine became a conditionally essential amino acid upon persistent therapeutic-dose clindamycin expose, evidenced by a dramatic decrease in intestinal glutamine level and glutaminase expression. Mechanistically, clindamycin substantially confounded the abundance of butyrate-producing strains, lead to the deficiency of fecal butyrate which is normally a fundamental fuel for enterocytes, and in turn increased compensatory use of glutamine. In addition to its pivotal roles in colonic epithelial cell turnover, glutamine was required for nitric oxide (NO) production in classic macrophage-driven host defense facilitating pathogen removal. Importantly, oral administration of glutamine effectively attenuated clindamycin-induced dysbiosis and restored intestinal barrier dysfunction in mice. Collectively, this study highlighted the importance of gut microbiota in host energy homeostasis, and provided a rationale for introducing glutamine supplementation to patients receiving long-term antibiotic treatment.
    Keywords:  Clindamycin; Glutamine; Gut microbial dysbiosis; Intestinal barrier dysfunction
    DOI:  https://doi.org/10.1017/S0007114520004195
  6. Microb Genom. 2020 Oct 19.
    Azithromycin resistance mutations in Streptococcus pneumoniae as revealed by a chemogenomic screen.
    Hélène Gingras, Kévin Patron, Philippe Leprohon, Marc Ouellette.
      We report on the combination of chemical mutagenesis, azithromycin selection and next-generation sequencing (Mut-Seq) for the identification of small nucleotide variants that decrease the susceptibility of Streptococcus pneumoniae to the macrolide antibiotic azithromycin. Mutations in the 23S ribosomal RNA or in ribosomal proteins can confer resistance to macrolides and these were detected by Mut-Seq. By concentrating on recurrent variants, we could associate mutations in genes implicated in the metabolism of glutamine with decreased azithromycin susceptibility among S. pneumoniae mutants. Glutamine synthetase catalyses the transformation of glutamate and ammonium into glutamine and its chemical inhibition is shown to sensitize S. pneumoniae to antibiotics. A mutation affecting the ribosomal-binding site of a putative ribonuclease J2 is also shown to confer low-level resistance. Mut-Seq has the potential to reveal chromosomal changes enabling high resistance as well as novel events conferring more subtle phenotypes.
    Keywords:  Azithromycin; Glutamine; Resistance; Streptococcus pneumoniae; chemical mutagenesis; macrolide; next generation sequencing
    DOI:  https://doi.org/10.1099/mgen.0.000454
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