Therapeutic Strategies Impacting Cancer Cell Glutamine Metabolism

Lukey, Michael J.; Wilson, Kristin; Cerione, Richard A.

doi:10.4155/fmc.13.130

Cited by 126 publications

(110 citation statements)

References 122 publications

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“…The role of kidney-type glutaminase in cancer has been heavily investigated [7,[71][72][73][74][75][76][77]. The Cancer Genome Atlas (TCGA) pan-cancer gene expression data show high expression of GLS in acute myeloid leukemia, adrenocortical cancer, triple-negative breast cancer, colorectal cancer, kidney clear or papillary cell carcinoma, lung adenocarcinoma, melanoma, mesothelioma, pancreatic cancer, sarcoma and thyroid cancer [78,79].…”

Section: Kidney-type Glutaminase: Implications In Cancermentioning

confidence: 99%

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

2017

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Many cancer cells exhibit an altered metabolic phenotype, in which glutamine consumption is upregulated relative to healthy cells. This metabolic reprogramming often depends upon mitochondrial glutaminase activity, which converts glutamine to glutamate, a key precursor for biosynthetic and bioenergetic processes. Two isozymes of glutaminase exist, a kidney-type (GLS) and a liver-type enzyme (GLS2 or LGA). While a majority of studies have focused on GLS, here we summarize key findings on both glutaminases, describing their structure and function, their roles in cancer and pharmacological approaches to inhibiting their activities.

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Section: Kidney-type Glutaminase: Implications In Cancermentioning

confidence: 99%

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

2017

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“…Recent studies confirmed that SIRT4 indeed acts as a tumor suppressor, by repressing glutamine metabolism and promoting genomic stability (30,69,71). Glutamine is a key amino acid required for diverse intracellular processes such as macromolecular synthesis, redox homeostasis, oxidative metabolism, and many others (95). Although most mammalian cells can synthesize glutamine, under conditions of rapid cell proliferation, such as cancer, a steady extracellular source of glutamine becomes essential.…”

Section: Sirt4 Acts As a Tumor Suppressor Via Repression Of Glutaminementioning

confidence: 99%

“…Glutamine is initially hydrolyzed by glutamate synthase (GLS) to glutamate, which is then subsequently converted to a Krebs cycle intermediate, a-ketoglutarate, by the action of GDH (95). SIRT4 interacts with GDH in pancreatic b-cells and ADP-ribosylates GDH to repress its activity (52).…”

Section: Sirt4 Suppresses Glutamate Dehydrogenase Activitymentioning

confidence: 99%

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

132

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Significance: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors. Recent Advances: New work has illuminated multiple links between mitochondrial sirtuins and cancer. SIRT5 has been shown to regulate the recently described post-translational modifications succinyl-lysine, malonyllysine, and glutaryl-lysine. An understanding of these modifications is still in its infancy. Enumeration of SIRT3 and SIRT5 targets via advanced proteomic techniques promises to dramatically enhance insight into functions of these proteins. Critical Issues: In this review, we highlight the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis. Furthermore, we discuss emerging roles for mitochondrial sirtuins in suppressing and/or promoting tumorigenesis, depending on the cellular and molecular context. Future Directions: Currently, hundreds of potential SIRT3 and SIRT5 molecular targets have been identified in proteomic experiments. Future studies will need to validate the major targets of these enzymes, and elucidate how acetylation and/or acylation modulate their functionality. A great deal of interest exists in targeting sirtuins pharmacologically; this endeavor will require development of sirtuin-specific modulators (activators and inhibitors) as potential treatments for cancer and metabolic disease. Antioxid.

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“…17 However, activity in patients with recurrent malignant glioma was low. 18 More recently, therapeutic approaches targeting amino acid transport were suggested including for example inhibition of the glutamine transporter SLC1A5 15 and inhibition of the glutamate-cystine antiporter xCT. 19 Much of the renewed interest in therapeutically targeting of glutamine metabolism is related to the first step of glutamine utilization, the conversion of glutamine to glutamate by the enzyme glutaminase.…”

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confidence: 99%

“…21 Properties of the new glutaminase inhibitors are extensively reviewed in the recent literature. 15,22 Both agents specifically inhibit the GLS isoenzyme (both splice variants KGA and GAC) and act by allosteric binding to the protein.…”

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confidence: 99%

Glutamate enrichment as new diagnostic opportunity in breast cancer

Budczies

Pfitzner

Győrffy

et al. 2014

Intl Journal of Cancer

114

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Exogenous glutamine is an important source of energy and molecular building blocks for many tumors. There is a renewed interest in therapeutically targeting glutamine metabolism due to the recent discovery of two novel glutaminase inhibitors. To quantify the dysregulation of the glutamate-glutamine equilibrium in breast cancer, metabolomics analysis of 270 clinical breast cancer samples and 97 normal breast samples was carried out using gas chromatography combined with time-of-flight mass spectrometry. Positive correlation between glutamate and glutamine in normal breast tissues switched to negative correlation between glutamate and glutamine in breast cancer tissues. Compared with the ratio of glutamate to glutamine in normal tissues, we found 56% of the ER1 tumor tissues and 88% of the ER2 tumor tissues glutamate-enriched. The glutamateto-glutamine ratio (GGR) significantly correlated with ER status (p 5 8.0E-09) and with tumor grade (p 5 3.3E-05). Higher levels of GGR were associated with prolonged overall survival in univariate analysis (HR 5 0.77, p 5 0.027) and in multivariate analysis (HR 5 0.73, p 5 0.038). GGR levels were reflected in an unsupervised clustering of metabolomics profiles. In a supervised analysis of metabolomics data and of genome-wide expression data, replacement of GGR by metabolite surrogate markers was feasible, while replacement of GGR by RNA markers had a limited accuracy. Functional analysis of the gene expression data showed negative correlation between glutamate enrichment and activation of peroxisome proliferator-activated receptor (PPAR) pathway. Our findings may have important implications for patient stratification related to utilization of glutaminase inhibitors.Altered energy metabolism is acknowledged as one of the emerging hallmarks of cancer. 1 Recently, there is a renewed interest in the metabolic transformation occurring in cancer cells and in targeting metabolic enzymes for cancer therapy. 2-4 However, the discovery of dysregulated metabolism in tumors dates back to the work of Otto Warburg in the 1920s. Warburg observed that cancer cells exhibit elevated glycolysis and that much of the generated pyruvate is fermented to lactate rather than feed to the TCA cycle and used for oxidative phosphorylation. 5,6 This phenomenon occurs under anaerobic and even under aerobic conditions ("aerobic glycolysis").A second change that occurs in central metabolism of many cancer cells is the alteration of glutamine metabolism. 7-9 Glutamine can be used to replenish the TCA cycle instead of glucose and feed in carbon and nitrogen for synthesis of nucleotides, several amino acids and glutathione. Further, glutamine can be used for energy production and in transformed cultured cells glutamine driven oxidative phosphorylation was recently shown to be the main source of

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Therapeutic Strategies Impacting Cancer Cell Glutamine Metabolism

Cited by 126 publications

References 122 publications

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Glutamate enrichment as new diagnostic opportunity in breast cancer

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