Plasma glutamate concentration and lymphocyte activity

Dröge, Wulf; Eck, Hans‐Peter; Betzler, M.; Schlag, Peter M.; Drings, P.; Ébert, W.

doi:10.1007/bf00417824

Cited by 63 publications

(31 citation statements)

References 15 publications

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“…43 Thus, we measured cystine uptake, which enters the cell through the Na ϩ -independent x c Ϫ system in exchange for glutamate, 43 and found that it was similar in the 3 melanoma cell lines (see Results). However, if extracellular levels of glutamate are high, as may occur in patients with advanced cancer, 44 cystine uptake is competitively inhibited, decreasing intracellular cystine availability. Then, cysteine released from extracellular GSH by GGT may represent a fundamental difference.…”

Section: Discussionmentioning

confidence: 99%

γ-Glutamyl transpeptidase overexpression increases metastatic growth of B16 melanoma cells in the mouse liver

et al. 2002

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B16 melanoma (B16M) cells with high glutathione (GSH) content show rapid proliferation in vitro and high metastatic activity in the liver in vivo. ␥-Glutamyl transpeptidase (GGT)-mediated extracellular GSH cleavage and intracellular GSH synthesis were studied in vitro in B16M cells with high (F10) and low (F1) metastatic potential. GGT activity was modified by transfection with the human GGT gene (B16MF1/Tet-GGT cells) or by acivicin-induced inhibition. B16MF1/Tet-GGT and B16MF10 cells exhibited higher GSH content (35 ؎ 6 and 40 ؎ 5 nmol/10 6 cells, respectively) and GGT activity (89 ؎ 9 and 37 ؎ 7 mU/10 6 cells, respectively) as compared (P < .05) with B16MF1 cells (10 ؎ 3 nmol GSH and 4 mU GGT/10 6 cells). Metastasis (number of foci/100 mm 3 of liver) increased in B16MF1 cells pretreated with GSH ester (ϳ3-fold, P < .01), and decreased in B16MF1/Tet-GGT and B16MF10 cells pretreated with the GSH synthesis inhibitor L-buthionine (S,R)-sulphoximine (ϳ5-fold and 2-fold, respectively, P < .01). Liver, kidney, brain, lung, and erythrocyte GSH content in B16MF1/Tet-GGT-or B16MF10-bearing mice decreased as compared with B16MF1-and non-tumor-bearing mice. Organic anion transporting polypeptide 1-independent sinusoidal GSH efflux from hepatocytes increased in B16MF1/Tet-GGT-or B16MF10-bearing mice (ϳ2-fold, P < . ␥ -Glutamyl-cysteinyl-glycine (GSH) is involved in many cellular functions, e.g., bioreductive reactions, maintenance of enzyme activity, amino acid transport, protection against oxidative/nitrosative stress, and detoxification of xenobiotics. 1 Induction of GSH deficiency in tumors was shown to be potentially useful in cancer therapy. 2 Elevation of intracellular GSH levels is associated with mitogenic stimulation 3 and regulation of DNA synthesis. 4 We found that GSH controls the onset of tumor-cell proliferation by regulating protein kinase C activity and intracellular pH, 5 and that a direct increase of intracellular GSH levels promotes survival and metastatic growth of B16M cells in the liver. 6,7 In rapidly growing tumors, cyst(e)ine, whose concentration in blood is low, may become limiting for GSH synthesis and cell growth. 8,9 Thus, malignant cells might require alternative pathways to ensure free cyst(e)ine availability. Recently, as it was shown in 3-methylcholantrene-induced sarcomas growing in rats, blood GSH can be used by solid tumors. 10 ␥-glutamyl transpeptidase (GGT) is the only known enzyme that cleaves the ␥-glutamyl-cysteine peptide bond in GSH and other ␥-glutamyl compounds. 11 GGT contains a heavy subunit (41.6 kd) that anchors the enzyme to the plasma membrane, and a light subunit (19.7 kd) orientated towards the outer surface of the cell membrane, which contains the catalytic site. 12 GGT cleaves GSH releasing ␥-glutamyl amino acids and cysteinylglycine, which is further cleaved by membrane-bound dipeptidases into cysteine and glycine. 13 Free ␥-glutamyl-amino acids, cysteine, and glycine entering the cell serve as GSH precursors. 8 Hence GGT expression may provide tumor cells with a gro...

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Section: Discussionmentioning

confidence: 99%

γ-Glutamyl transpeptidase overexpression increases metastatic growth of B16 melanoma cells in the mouse liver

et al. 2002

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“…Glutamate was reported to bind specific sites on T-lymphocyte plasma membranes and impair the activity of macrophages and lymphocytes in vitro (55)(56)(57). In carcinoma patients, elevated plasma glutamate levels were linked to a reduced lymphocyte response to mitogens and a high death rate (58,59).…”

Section: Analysis Of a Candidate Tumor Suppressor Gene On 6qmentioning

confidence: 99%

A Fluorescence in Situ Hybridization Map of 6q Deletions in Acute Lymphocytic Leukemia

et al. 2004

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With the objective of identifying candidate tumor suppressor genes, we used fluorescence in situ hybridization to map leukemia-related deletions of the long arm of chromosome 6 (6q). Twenty of 24 deletions overlapped to define a 4.8-Mb region of minimal deletion between markers D6S1510 and D6S1692 within chromosome 6 band q16. Using reverse transcription-PCR, we found evidence of expression in hematopoietic cells for 3 of 15 genes in the region (GRIK2, C6orf111, and CCNC). Comparison between our own and published deletion data singled out GRIK2 as the gene most frequently affected by deletions of 6q in acute lymphocytic leukemia (ALL). Sequence analysis of GRIK2 in 14 ALL cases carrying heterozygous 6q deletions revealed a constitutional and paternally inherited C to G substitution in exon 6 encoding for an amino acid change in one patient. The substitution was absent among 232 normal alleles tested, leaving open the possibility that heterozygous carriers of such mutations may be susceptible to ALL. Although low in all normal hematopoietic tissues, quantitative reverse transcription-PCR showed higher baseline GRIK2 expression in thymus and T cells than other lineages. Among T-cell ALL patients, 6q deletion was associated with a statistically significant reduction in GRIK2 expression (P ‫؍‬ 0.0001). By contrast, elevated GRIK2 expression was measured in the myelomonocytic line THP-1 and in one patient with common ALL. Finally, we detected significant levels of GRIK2 expression in prostate, kidney, trachea, and lung, raising the possibility that this gene may be protective against multiple tumor types.

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“…This is the case for patients with cancer (Dröge et al, 1988). It is believed that the metabolic properties of tumors combined with an altered metabolism in patients with cancer contribute to the abnormal L-glutamate plasma concentrations in these patients (Dröge et al, 1988).…”

Section: Mglu Receptors In Peripheral Tissuesmentioning

confidence: 99%

Exciting Times beyond the Brain: Metabotropic Glutamate Receptors in Peripheral and Non-Neural Tissues

Julio–Pieper

Flor²,

Dinan³

et al. 2011

Pharmacol Rev

165

135

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Plasma glutamate concentration and lymphocyte activity

Cited by 63 publications

References 15 publications

γ-Glutamyl transpeptidase overexpression increases metastatic growth of B16 melanoma cells in the mouse liver

γ-Glutamyl transpeptidase overexpression increases metastatic growth of B16 melanoma cells in the mouse liver

A Fluorescence in Situ Hybridization Map of 6q Deletions in Acute Lymphocytic Leukemia

Exciting Times beyond the Brain: Metabotropic Glutamate Receptors in Peripheral and Non-Neural Tissues

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