Lack of expression of the liver-type glutaminase (LGA) mRNA in human malignant gliomas

Szeliga, Monika; Sidoryk, Marta; Matyja, Ewa; Kowalczyk, Paweł; Albrecht, Jan

doi:10.1016/j.neulet.2004.10.051

Cited by 47 publications

(45 citation statements)

References 15 publications

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“…The overexpression of glutaminase is observed in other malignancies as well, such as liver, brain and breast tumors [60][61][62]. Of note, these tumors possess an active mitochondrial metabolism in vitro as characterized by other studies (see Section 3.1).…”

Section: Glutaminolysismentioning

confidence: 95%

Anaplerosis in cancer: Another step beyond the warburg effect

Ochoa-Ruiz¹,

Díaz-Ruiz²

2012

AJMB

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Biosynthesis is up-regulated in tumors and thus the demand for anabolic intermediates is increased. The metabolic routes providing the building blocks for macromolecules are thus a very attractive target as they are not normally up-regulated in a normal quiescent cell. Some routes for glycolysis-derived intermediates production have been identified, but these do not constitute the whole pool of biosynthetic molecules in the cell, as many of these derive from mitochondria in the Krebs cycle. Indeed, this metabolic pathway is considered a "biosynthetic hub" from which anabolism is fed. If a metabolite efflux is indeed occurring, anaplerotic reactions must keep a steady supply of substrates. In spite of this obvious relevance of anaplerosis, it has been poorly characterized in the malignant cell context. Glutaminolysis and and pyruvate carboxylation are two pathways that function in an anaplerotic fashion. In spite of the increasing evidence implicating these two processes in cancer metabolism their role as intermediate providers is overlooked. In this review we analyze the implications of an active anaplerosis in cancer and we discuss experimental evidence showing the relevance of these metabolic routes in tumor physiology.

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Section: Glutaminolysismentioning

confidence: 95%

Anaplerosis in cancer: Another step beyond the warburg effect

Ochoa-Ruiz¹,

Díaz-Ruiz²

2012

AJMB

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“…Recent studies have also stressed the importance of glutaminolysis in maintaining the malignant phenotype, providing indications that glutaminases may be potential therapeutic targets in some cancer cells (4,(10)(11)(12)(13). Elevated GAC mRNA levels have been detected in glyomas (14,15), colorectal carcinomas and adenomas (16), and breast tumor cell lines (7), when compared to normal cells. Gao and coworkers showed that c-Myc induces elevated GAC expression in both prostate cancer and B lymphoma cell lines as well as in prostate cancer tissues vs. normal (17).…”

mentioning

confidence: 99%

Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism

Cassago

Ferreira

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

234

288

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Glutamine is an essential nutrient for cancer cell proliferation, especially in the context of citric acid cycle anaplerosis. In this manuscript we present results that collectively demonstrate that, of the three major mammalian glutaminases identified to date, the lesser studied splice variant of the gene gls, known as Glutaminase C (GAC), is important for tumor metabolism. We show that, although levels of both the kidney-type isoforms are elevated in tumor vs. normal tissues, GAC is distinctly mitochondrial. GAC is also most responsive to the activator inorganic phosphate, the content of which is supposedly higher in mitochondria subject to hypoxia. Analysis of X-ray crystal structures of GAC in different bound states suggests a mechanism that introduces the tetramerization-induced lifting of a "gating loop" as essential for the phosphate-dependent activation process. Surprisingly, phosphate binds inside the catalytic pocket rather than at the oligomerization interface. Phosphate also mediates substrate entry by competing with glutamate. A greater tendency to oligomerize differentiates GAC from its alternatively spliced isoform and the cycling of phosphate in and out of the active site distinguishes it from the liver-type isozyme, which is known to be less dependent on this ion.glutamine metabolism | Warburg effect

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“…Much of the interest in glutaminase has stemmed from its association with various cancers, where glutaminase activity is hypothesized to be critical in tumor growth and a potential target for treatment (162,163). Various tumors have been linked to glutaminase overexpression (164)(165)(166)(167). These findings indicate the potential for isoform specific regulation of glutaminase in various circumstances.…”

Section: Glutaminasementioning

confidence: 99%

“…Glutaminase is generally localized to the inner membrane of the mitochondria (172)(173)(174); although additional studies have recognized a nuclear population of glutaminase (159,167). Increase in amount, activity or release of glutaminase could facilitate uncontrolled generation of glutamate in the CNS extracellular space.…”

Section: Glutaminasementioning

confidence: 99%

Potentiation of excitotoxicity in HIV-1-associated Dementia and the significance of glutaminase

Erdmann¹,

Whitney²,

Zheng³

2006

Clinical Neuroscience Research

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HIV-1 Associated Dementia (HAD) is a significant consequence of HIV infection. Although multiple inflammatory factors contribute to this chronic, progressive dementia, excitotoxic damage appears to be an underlying mechanism in the neurodegenerative process. Excitotoxicity is a cumulative effect of multiple processes occurring in the CNS during HAD. The overstimulation of glutamate receptors, an increased vulnerability of neurons, and disrupted astrocyte support each potentiate excitotoxic damage to neurons. Recent evidence suggests that poorly controlled generation of glutamate by phosphate-activated glutaminase may contribute to the neurotoxic state typical of HAD as well as other neurodegenerative disorders. Glutaminase converts glutamine, a widely available substrate throughout the CNS to glutamate. Inflammatory conditions may precipitate unregulated activity of glutaminase, a potentially important mechanism in HAD pathogenesis.

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Lack of expression of the liver-type glutaminase (LGA) mRNA in human malignant gliomas

Cited by 47 publications

References 15 publications

Anaplerosis in cancer: Another step beyond the warburg effect

Anaplerosis in cancer: Another step beyond the warburg effect

Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism

Potentiation of excitotoxicity in HIV-1-associated Dementia and the significance of glutaminase

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