Effect of Acidosis on the Properties of the Glutaminase mRNA pH-Response Element Binding Protein

Laterza, Omar; Curthoys, Norman P.

doi:10.1681/asn.v1191583

Cited by 18 publications

(1 citation statement)

References 22 publications

(20 reference statements)

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“…Thus, inhibition of GLS1 via 968 prevented cancer cells from being able to compensate for the acidification of their culturing media and caused them to become more sensitive to glutamine withdrawal. Moreover, Wagner and Curthoys independently showed that GLS1 expression is up-regulated in mice suffering from chronic acidosis, which is consistent with earlier findings showing that the mRNA encoding GLS1 contains a pH-responsive element that helps promote the stability of the transcript when exposed to acidic conditions. − …”

Section: Introductionsupporting

confidence: 85%

Simultaneously Targeting Tissue Transglutaminase and Kidney Type Glutaminase Sensitizes Cancer Cells to Acid Toxicity and Offers New Opportunities for Therapeutic Intervention

2014

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Most cancer cells undergo characteristic metabolic changes that are commonly referred to as the Warburg effect, with one of the hallmarks being a dramatic increase in the rate of lactic acid fermentation. This leads to the production of protons, which in turn acidifies the microenvironment surrounding tumors. Cancer cells have acquired resistance to acid toxicity, allowing them to survive and grow under these detrimental conditions. Kidney type glutaminase (GLS1), which is responsible for the conversion of glutamine to glutamate, produces ammonia as part of its catalytic activities and has been shown to modulate cellular acidity. In this study, we show that tissue, or type 2, transglutaminase (TG2), a γ-glutamyl transferase that is highly expressed in metastatic cancers and produces ammonia as a byproduct of its catalytic activity, is up-regulated by decreases in cellular pH and helps protect cells from acid-induced cell death. Since both TG2 and GLS1 can similarly function to protect cancer cells, we then proceeded to demonstrate that treatment of a variety of cancer cell types with inhibitors of each of these proteins results in synthetic lethality. The combination doses of the inhibitors induce cell death, while individual treatment with each compound shows little or no ability to kill cells. These results suggest that combination drug treatments that simultaneously target TG2 and GLS1 might provide an effective strategy for killing cancer cells.

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Section: Introductionsupporting

confidence: 85%

Simultaneously Targeting Tissue Transglutaminase and Kidney Type Glutaminase Sensitizes Cancer Cells to Acid Toxicity and Offers New Opportunities for Therapeutic Intervention

2014

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Glutamine metabolism: Role in acid‐base balance*

Taylor

Curthoys

2004

Biochem Molecular Bio Educ

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108

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The intent of this review is to provide a broad overview of the interorgan metabolism of glutamine and to discuss in more detail its role in acid-base balance. Muscle, adipose tissue, and the lungs are the primary sites of glutamine synthesis and release. During normal acid-base balance, the small intestine and the liver are the major sites of glutamine utilization. The periportal hepatocytes catabolize glutamine and convert ammonium and bicarbonate ions to urea. In contrast, the perivenous hepatocytes are capable of synthesizing glutamine. During metabolic acidosis, the kidney becomes the major site of glutamine extraction and catabolism. This process generates ammonium ions that are excreted in the urine to facilitate the excretion of acids and bicarbonate ions that are transported to the blood to partially compensate the acidosis. The increased renal extraction of glutamine is balanced by an increased release from muscle and liver and by a decreased utilization in the intestine. During chronic acidosis, this adaptation is sustained, in part, by increased renal expression of genes that encode various transport proteins and key enzymes of glutamine metabolism. The increased levels of phosphoenolpyruvate carboxykinase result from increased transcription, while the increase in glutaminase and glutamate dehydrogenase activities result from stabilization of their respective mRNAs. Where feasible, this review draws upon data obtained from studies in humans. Studies conducted in model animals are discussed where available data from humans is either lacking or not firmly established. Because there are quantitative differences in tissue utilization and synthesis of glutamine in different mammals, the review will focus more on common principles than on quantification.Keywords: Glutamine, metabolic acidosis, glutaminase, glutamine synthetase, phosphoenolpyruvate carboxykinase.The structure and function of proteins and of macromolecular complexes are critically dependent upon the hydrogen ion concentration of the surrounding medium. As a result, higher eukaryotes maintain the pH of the extracellular fluid and of various intracellular compartments within narrow limits. For example in humans, normal arterial plasma pH is 7.40 Ϯ 0.05. Fluctuations in excess of 0.5 pH units from this value are usually lethal. Thus, the maintenance of normal acid-base balance is essential for survival. The major acid generated as a byproduct of catabolism is CO 2 . A normal individual generates ϳ20 mol of CO 2 per day. However, this acid is volatile and is readily expelled by the lungs. The relative concentrations of HCO 3 Ϫ and CO 2 are the primary determinants of plasma pH. The HCO 3 Ϫ / CO 2 system has a pK of 6.1 and would appear to be a relatively ineffective buffer at pH 7.4. This system is made effective by the ability to maintain a constant CO 2 concentration through changes in the rate of respiration. Various diseases of the lung or disorders of the central nervous system can result in either hypo-or hyperventilation [1]. The former c...

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Real time non‐invasive imaging of receptor–ligand interactions in vivo

Winnard

Raman

2003

J of Cellular Biochemistry

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Non-invasive longitudinal detection and evaluation of gene expression in living animals can provide investigators with an understanding of the ontogeny of a gene's biological function(s). Currently, mouse model systems are used to optimize magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and optical imaging modalities to detect gene expression and protein function. These molecular imaging strategies are being developed to assess tumor growth and the tumor microenvironment. In addition, pre-labeling of progenitor cells can provide invaluable information about the developmental lineage of stem cells both in organogenesis and tumorigenesis. The feasibility of this approach has been extensively tested by targeting of endogenous tumor cell receptors with labeled ligand (or ligand analog) reporters and targeting enzymes with labeled substrate (or substrate analog). We will primarily discuss MRI, PET, and SPECT imaging of cell surface receptors and the feasibility of non-invasive imaging of gene expression using the tumor microenvironment (e.g., hypoxia) as a conditional regulator of gene expression.

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Effect of Acidosis on the Properties of the Glutaminase mRNA pH-Response Element Binding Protein

Cited by 18 publications

References 22 publications

Simultaneously Targeting Tissue Transglutaminase and Kidney Type Glutaminase Sensitizes Cancer Cells to Acid Toxicity and Offers New Opportunities for Therapeutic Intervention

Simultaneously Targeting Tissue Transglutaminase and Kidney Type Glutaminase Sensitizes Cancer Cells to Acid Toxicity and Offers New Opportunities for Therapeutic Intervention

Glutamine metabolism: Role in acid‐base balance*

Real time non‐invasive imaging of receptor–ligand interactions in vivo

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