scholarly journals Drivers of Glucose and Glutamine Metabolism Reprogramming in Tumor Cells and Their Potential as Target for Cancer

2018 ◽  
Vol 04 (02) ◽  
Author(s):  
Abraham Nigussie Mekuria ◽  
Abraham Degaga Abdi
Keyword(s):  
Tumor Cells ◽  
Glutamine Metabolism

scholarly journals Causes and Consequences of A Glutamine Induced Normoxic HIF1 Activity for the Tumor Metabolism

2019 ◽  
Vol 20 (19) ◽  
pp. 4742 ◽  
Author(s):  
Matthias Kappler ◽  
Ulrike Pabst ◽  
Claus Weinholdt ◽  
Helge Taubert ◽  
Swetlana Rot ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ascorbic Acid ◽  
Amino Acid ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Glutamine Metabolism ◽  
Dependent Manner ◽  
Acetyl Coa ◽  
Hypoxic Conditions

The transcription factor hypoxia-inducible factor 1 (HIF1) is the crucial regulator of genes that are involved in metabolism under hypoxic conditions, but information regarding the transcriptional activity of HIF1 in normoxic metabolism is limited. Different tumor cells were treated under normoxic and hypoxic conditions with various drugs that affect cellular metabolism. HIF1α was silenced by siRNA in normoxic/hypoxic tumor cells, before RNA sequencing and bioinformatics analyses were performed while using the breast cancer cell line MDA-MB-231 as a model. Differentially expressed genes were further analyzed and validated by qPCR, while the activity of the metabolites was determined by enzyme assays. Under normoxic conditions, HIF1 activity was significantly increased by (i) glutamine metabolism, which was associated with the release of ammonium, and it was decreased by (ii) acetylation via acetyl CoA synthetase (ACSS2) or ATP citrate lyase (ACLY), respectively, and (iii) the presence of L-ascorbic acid, citrate, or acetyl-CoA. Interestingly, acetylsalicylic acid, ibuprofen, L-ascorbic acid, and citrate each significantly destabilized HIF1α only under normoxia. The results from the deep sequence analyses indicated that, in HIF1-siRNA silenced MDA-MB-231 cells, 231 genes under normoxia and 1384 genes under hypoxia were transcriptionally significant deregulated in a HIF1-dependent manner. Focusing on glycolysis genes, it was confirmed that HIF1 significantly regulated six normoxic and 16 hypoxic glycolysis-associated gene transcripts. However, the results from the targeted metabolome analyses revealed that HIF1 activity affected neither the consumption of glucose nor the release of ammonium or lactate; however, it significantly inhibited the release of the amino acid alanine. This study comprehensively investigated, for the first time, how normoxic HIF1 is stabilized, and it analyzed the possible function of normoxic HIF1 in the transcriptome and metabolic processes of tumor cells in a breast cancer cell model. Furthermore, these data imply that HIF1 compensates for the metabolic outcomes of glutaminolysis and, subsequently, the Warburg effect might be a direct consequence of the altered amino acid metabolism in tumor cells.

Effect of palmitate, acetate and glucose on glutamine metabolism in Ehrlich ascites tumor cells

Biochimie ◽  
1988 ◽  
Vol 70 (6) ◽  
pp. 833-834 ◽  
Author(s):  
Miguel A. Medina ◽  
Francisca Sánchez-Jiménez ◽  
Ana R. Quesada ◽  
F.Javier Márquez ◽  
Ignacio Núñez de Castro
Keyword(s):  
Tumor Cells ◽  
Ehrlich Ascites Tumor ◽  
Glutamine Metabolism ◽  
Ehrlich Ascites Tumor Cells ◽  
Ascites Tumor ◽  
Ehrlich Ascites

scholarly journals Ionizing Radiation Upregulates Glutamine Metabolism and Induces Cell Death via Accumulation of Reactive Oxygen Species

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Pengfei Yang ◽  
Xiangxia Luo ◽  
Jin Li ◽  
Tianyi Zhang ◽  
Xiaoling Gao ◽  
...  
Keyword(s):  
Cell Death ◽  
Ionizing Radiation ◽  
Tumor Cells ◽  
Metabolic Flux ◽  
Glutamine Metabolism ◽  
X Rays ◽  
Ros Accumulation ◽  
Intracellular Ros ◽  
Radiation Induced ◽  
Excessive Accumulation

Glutamine metabolism provides energy to tumor cells and also produces reactive oxygen species (ROS). Excessive accumulation of ROS can damage mitochondria and eventually lead to cell death. xCT (SLC7A11) is responsible for the synthesis of glutathione in order to neutralize ROS. In addition, mitophagy can remove damaged mitochondria to keep the cell alive. Ionizing radiation kills tumor cells by causing the accumulation of ROS, which subsequently induces nuclear DNA damage. With this in mind, we explored the mechanism of intracellular ROS accumulation induced by ionizing radiation and hypothesized new methods to enhance the effect of radiotherapy. We used MCF-7 breast cancer cells and HCT116 colorectal cancer cells in our study. The above-mentioned cells were irradiated with different doses of X-rays or carbon ions. Clone formation assays were used to detect cell proliferation, enzyme-linked immunosorbent assay (ELISA) detected ATP, and glutathione (GSH) production, while the expression of proteins was detected by Western blot and quantitative real-time PCR analysis. The production of ROS was detected by flow cytometry, and immunofluorescence was used to track mitophagy-related processes. Finally, BALB/C tumor-bearing nude mice were irradiated with X-rays in order to further explore the protein expression found in tumors with the use of immunohistochemistry. Ionizing radiation increased the protein expressions of ASCT2, GLS, and GLUD in order to upregulate the glutamine metabolic flux in tumor cells. This caused an increase in ATP secretion. Meanwhile, ionizing radiation inhibited the expression of the xCT (SLC7A11) protein and reduced the generation of glutathione, leading to excessive accumulation of intracellular ROS. The mitophagy inhibitor, or knockdown Parkin gene, is able to enhance the ionizing radiation-induced ROS production and increase nucleus DNA damage. This combined treatment can significantly improve the killing effect of radiation on tumor cells. We concluded that ionizing radiation could upregulate the glutamine metabolic flux and enhance ROS accumulation in mitochondria. Ionizing radiation also decreased the SLC7A11 expression, resulting in reduced GSH generation. Therefore, inhibition of mitophagy can increase ionizing radiation-induced cell death.

scholarly journals Glutamine metabolism in the proliferation of GS-expression pituitary tumor cells

2020 ◽  
Vol 9 (3) ◽  
pp. 223-233
Author(s):  
Jintao Hu ◽  
Qingbo Chen ◽  
Xiao Ding ◽  
Xin Zheng ◽  
Xuefeng Tang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Lines ◽  
Pituitary Tumor ◽  
Nucleotide Metabolism ◽  
Glutamine Metabolism ◽  
Expression Level ◽  
Main Role ◽  
Ki 67

Objective Many cancer cells cannot survive without exogenous glutamine (Gln); however, cancer cells expressing glutamine synthetase (GS) do not have this restriction. Previous metabolomics studies have indicated that glutamine metabolism is altered during pituitary tumorigenesis. However, the main role of Gln in pituitary adenoma (PA) pathophysiology remains unknown. The aim of this study was to evaluate the expression of GS and the main role of Gln in human PAs. Methods We used cell proliferation assay and flow cytometry to assess the effect of Gln depletion on three different pituitary cell lines and human primary PA cells. We then investigated the expression level of Gln synthetase (GS) in 24 human PA samples. At last, we used LC-MS/MS to identify the differences in metabolites of PA cells after the blockage of both endogenous and exogenous Gln. Results PA cell lines showed different sensitivities to Gln starvation, and the sensitivity is correlated with GS expression level. GS expressed in 21 out of the 24 human PA samples. Furthermore, a positive p53 and ki-67 index was correlated with a higher GS expression level (P < 0.05). Removal of both endogenous and exogenous Gln from GS-expressing PA cells resulted in blockage of nucleotide metabolism and cell cycle arrest. Conclusions Our data indicate that GS is needed for PA cells to undergo proliferation during Gln deprivation, and most human PA cells express GS and might have a negative response to exogenous Gln depletion. Moreover, Gln is mainly responsible for nucleotide metabolism in the proliferation of GS-expressing pituitary tumor cells.

scholarly journals Coordinative Metabolism of Glutamine Carbon and Nitrogen in proliferating Cancer Cells Under Hypoxia

2018 ◽  
Author(s):  
Yuanyuan Wang ◽  
Changsen Bai ◽  
Yuxia Ruan ◽  
Miao Liu ◽  
Qiaoyun Chu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Metabolic Pathway ◽  
Metabolic Flux ◽  
Glutamine Metabolism ◽  
Comprehensive Understanding ◽  
Nucleotide Biosynthesis ◽  
Acetyl Coenzyme A ◽  
Carbon And Nitrogen

ABSTRACTUnder hypoxia, most of glucose is converted to secretory lactate, which leads to the lack of carbon source from glucose and thus the overuse of glutamine-carbon. However, under such a condition how glutamine nitrogen is disposed to avoid releasing potentially toxic ammonia remains to be determined. Here we identify a metabolic flux of glutamine to secretory dihydroorotate under hypoxia. We found that glutamine nitrogen is indispensable to nucleotide biosynthesis, but enriched in dihyroorotate and orotate rather than processing to its downstream uridine monophosphate under hypoxia. Dihyroorotate, not orotate, is then secreted out of cells. The specific metabolic pathway occurs in vivo and is required for tumor growth. Such a metabolic pathway renders glutamine mainly to acetyl coenzyme A for lipogenesis, with the rest carbon and nitrogen being safely removed. Our results reveal how glutamine carbon and nitrogen are coordinatively metabolized under hypoxia, and provide a comprehensive understanding on glutamine metabolism.SignificanceTumor cells often addict to glutamine, and particularly utilize its carbon for lipogenesis under hypoxia. We reveal that tumor cells package the excessive glutamine-nitrogen into secretory dihydroorotate, instead of toxic ammonia. This specifically reprogrammed pathway supports in vivo tumor growth, and could offer diagnostic markers and therapeutic targets for cancers.

Abstract 1850: Role of microRNAs in circulating tumor cells glutamine metabolism pathways

2019 ◽  
Author(s):  
Ziwen Zhu ◽  
Sarah N. Owen ◽  
Abhinav Achreja ◽  
Sunitha Nagrath ◽  
Deepak Nagrath
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Glutamine Metabolism

scholarly journals Glutamine Metabolism in Brain Tumors

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1628 ◽  
Author(s):  
Siva Kumar Natarajan ◽  
Sriram Venneti
Keyword(s):  
Brain Tumors ◽  
Tumor Cells ◽  
Redox Homeostasis ◽  
Critical Role ◽  
Lipid Synthesis ◽  
Glutamine Metabolism ◽  
Glutamatergic Neurons ◽  
Non Invasive ◽  
Brain Tumor Cells ◽  
The Brain

Altered metabolism is a hallmark of cancer cells. Tumor cells rewire their metabolism to support their uncontrolled proliferation by taking up nutrients from the microenvironment. The amino acid glutamine is a key nutrient that fuels biosynthetic processes including ATP generation, redox homeostasis, nucleotide, protein, and lipid synthesis. Glutamine as a precursor for the neurotransmitter glutamate, and plays a critical role in the normal functioning of the brain. Brain tumors that grow in this glutamine/glutamate rich microenvironment can make synaptic connections with glutamatergic neurons and reprogram glutamine metabolism to enable their growth. In this review, we examine the functions of glutamate/glutamine in the brain and how brain tumor cells reprogram glutamine metabolism. Altered glutamine metabolism can be leveraged to develop non-invasive imaging strategies and we review these imaging modalities. Finally, we examine if targeting glutamine metabolism could serve as a therapeutic strategy in brain tumors.

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