 |
 Previous Article | Next Article 
The Journal of Neuroscience, December 15, 1999, 19(24):10767-10777
Compromised Glutamate Transport in Human Glioma Cells:
Reduction-Mislocalization of Sodium-Dependent Glutamate
Transporters and Enhanced Activity of Cystine-Glutamate Exchange
Zu-Cheng
Ye1,
Jeffrey
D.
Rothstein2, and
Harald
Sontheimer1
1 Department of Neurobiology, The University of Alabama
at Birmingham, Birmingham, Alabama 35294, and
2 Department of Neurology, Johns Hopkins University,
Baltimore, Maryland 21287
Elevated levels of extracellular glutamate
([Glu]o) can induce seizures and cause excitotoxic
neuronal cell death. This is normally prevented by astrocytic glutamate
uptake. Neoplastic transformation of human astrocytes causes malignant
gliomas, which are often associated with seizures and neuronal
necrosis. Here, we show that Na+-dependent glutamate
uptake in glioma cell lines derived from human tumors (STTG-1, D-54MG,
D-65MG, U-373MG, U-251MG, U-138MG, and CH-235MG) is up to 100-fold
lower than in astrocytes. Immunohistochemistry and subcellular
fractionation show very low expression levels of the astrocytic
glutamate transporter GLT-1 but normal expression levels of another
glial glutamate transporter, GLAST. However, in glioma cells,
essentially all GLAST protein was found in cell nuclei rather than the
plasma membrane. Similarly, brain tissues from glioblastoma patients
also display reduction of GLT-1 and mislocalization of GLAST. In glioma
cell lines, over 50% of glutamate transport was
Na+-independent and mediated by a
cystine-glutamate exchanger (system xc ). Extracellular
L-cystine dose-dependently induced glutamate release from
glioma cells. Glutamate release was enhanced by extracellular glutamine
and inhibited by (S)-4-carboxyphenylglycine, which
blocked cystine-glutamate exchange. These data suggest that the
unusual release of glutamate from glioma cells is caused by
reduction-mislocalization of Na+-dependent
glutamate transporters in conjunction with upregulation of
cystine-glutamate exchange. The resulting glutamate release from
glioma cells may contribute to tumor-associated necrosis and possibly
to seizures in peritumoral brain tissue.
Key words:
brain tumor; glutamate transporter; glutamate release; cystine-glutamate exchange; system
xc; excitotoxicity; epilepsy
Copyright © 1999 Society for Neuroscience 0270-6474/99/192410767-11$05.00/0
This article has been cited by other articles:
|
|
|
|
 
Y. Piao, L. Lu, and J. de Groot
AMPA receptors promote perivascular glioma invasion via {beta}1 integrin-dependent adhesion to the extracellular matrix
Neuro-oncol,
January 1, 2009;
11(3):
260 - 273.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Lyons, W. J. Chung, A. K. Weaver, T. Ogunrinu, and H. Sontheimer
Autocrine Glutamate Signaling Promotes Glioma Cell Invasion
Cancer Res.,
October 1, 2007;
67(19):
9463 - 9471.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Y. Shih, H. Erb, X. Sun, S. Toda, P. W. Kalivas, and T. H. Murphy
Cystine/Glutamate Exchange Modulates Glutathione Supply for Neuroprotection from Oxidative Stress and Cell Proliferation
J. Neurosci.,
October 11, 2006;
26(41):
10514 - 10523.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Huang, Z. Dai, C. Barbacioru, and W. Sadee
Cystine-Glutamate Transporter SLC7A11 in Cancer Chemosensitivity and Chemoresistance
Cancer Res.,
August 15, 2005;
65(16):
7446 - 7454.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. J. Chung, S. A. Lyons, G. M. Nelson, H. Hamza, C. L. Gladson, G. Y. Gillespie, and H. Sontheimer
Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors
J. Neurosci.,
August 3, 2005;
25(31):
7101 - 7110.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Arcella, G. Carpinelli, G. Battaglia, M. D'Onofrio, F. Santoro, R. T. Ngomba, V. Bruno, P. Casolini, F. Giangaspero, and F. Nicoletti
Pharmacological blockade of group II metabotropic glutamate receptors reduces the growth of glioma cells in vivo
Neuro-oncol,
July 1, 2005;
7(3):
236 - 245.
[Abstract]
[PDF]
|
|
|
|
|
|
|
R. I. Melendez, J. Vuthiganon, and P. W. Kalivas
Regulation of Extracellular Glutamate in the Prefrontal Cortex: Focus on the Cystine Glutamate Exchanger and Group I Metabotropic Glutamate Receptors
J. Pharmacol. Exp. Ther.,
July 1, 2005;
314(1):
139 - 147.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Cavelier and D. Attwell
Tonic release of glutamate by a DIDS-sensitive mechanism in rat hippocampal slices
J. Physiol.,
April 15, 2005;
564(2):
397 - 410.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. F. de Groot, T. J. Liu, G. Fuller, and W.K. A. Yung
The Excitatory Amino Acid Transporter-2 Induces Apoptosis and Decreases Glioma Growth In vitro and In vivo
Cancer Res.,
March 1, 2005;
65(5):
1934 - 1940.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Kalandadze, Y. Wu, K. Fournier, and M. B. Robinson
Identification of Motifs Involved in Endoplasmic Reticulum Retention-Forward Trafficking of the GLT-1 Subtype of Glutamate Transporter
J. Neurosci.,
June 2, 2004;
24(22):
5183 - 5192.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-C. Ye, M. S. Wyeth, S. Baltan-Tekkok, and B. R. Ransom
Functional Hemichannels in Astrocytes: A Novel Mechanism of Glutamate Release
J. Neurosci.,
May 1, 2003;
23(9):
3588 - 3596.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Deshane, C. C. Garner, and H. Sontheimer
Chlorotoxin Inhibits Glioma Cell Invasion via Matrix Metalloproteinase-2
J. Biol. Chem.,
January 31, 2003;
278(6):
4135 - 4144.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Baker, Z.-X. Xi, H. Shen, C. J. Swanson, and P. W. Kalivas
The Origin and Neuronal Function of In Vivo Nonsynaptic Glutamate
J. Neurosci.,
October 15, 2002;
22(20):
9134 - 9141.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Sato, M. Tamba, S. Okuno, K. Sato, K. Keino-Masu, M. Masu, and S. Bannai
Distribution of Cystine/Glutamate Exchange Transporter, System xc-, in the Mouse Brain
J. Neurosci.,
September 15, 2002;
22(18):
8028 - 8033.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Disease Mechanisms in Neuroscience
Neuroscientist,
February 1, 2002;
8(1):
5 - 5.
[PDF]
|
|
|
|
|
|
|
Z.-X. Xi, D. A. Baker, H. Shen, D. S. Carson, and P. W. Kalivas
Group II Metabotropic Glutamate Receptors Modulate Extracellular Glutamate in the Nucleus Accumbens
J. Pharmacol. Exp. Ther.,
January 1, 2002;
300(1):
162 - 171.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A.-C. Rimaniol, P. Mialocq, P. Clayette, D. Dormont, and G. Gras
Role of glutamate transporters in the regulation of glutathione levels in human macrophages
Am J Physiol Cell Physiol,
December 1, 2001;
281(6):
C1964 - C1970.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C Munch, A Penndorf, B Schwalenstocker, D Troost, A C Ludolph, P Ince, and T Meyer
Impaired RNA splicing of 5'-regulatory sequences of the astroglial glutamate transporter EAAT2 in human astrocytoma
J. Neurol. Neurosurg. Psychiatry,
November 1, 2001;
71(5):
675 - 678.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. B. Ransom, J. T. O'Neal, and H. Sontheimer
Volume-Activated Chloride Currents Contribute to the Resting Conductance and Invasive Migration of Human Glioma Cells
J. Neurosci.,
October 1, 2001;
21(19):
7674 - 7683.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. MARKERT, C. M. FULLER, G. Y. GILLESPIE, J. K. BUBIEN, L. A. MCLEAN, R. L. HONG, K. LEE, S. R. GULLANS, T. B. MAPSTONE, and D. J. BENOS
Differential gene expression profiling in human brain tumors
Physiol Genomics,
February 7, 2001;
5(1):
21 - 33.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. N. MacFarlane and H. Sontheimer
Modulation of Kv1.5 Currents by Src Tyrosine Phosphorylation: Potential Role in the Differentiation of Astrocytes
J. Neurosci.,
July 15, 2000;
20(14):
5245 - 5253.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
