Phosphoinositide 3-kinases upregulate system xc(-) via eukaryotic initiation factor 2α and activating transcription factor 4 - A pathway active in glioblastomas and epilepsy.
OBJECTIVE
Phosphoinositide 3-kinases (PI3Ks) relay growth factor signaling and mediate cytoprotection and cell growth. The cystine/glutamate antiporter system xc(-) imports cystine while exporting glutamate, thereby promoting glutathione synthesis while increasing extracellular cerebral glutamate. The aim of this study was to analyze the pathway through which growth factor and PI3K signaling induce the cystine/glutamate antiporter system xc(-) and to demonstrate its biological significance for neuroprotection, cell growth, and epilepsy.


RESULTS
PI3Ks induce system xc(-) through glycogen synthase kinase 3β (GSK-3β) inhibition, general control non-derepressible-2-mediated eukaryotic initiation factor 2α phosphorylation, and the subsequent translational up-regulation of activating transcription factor 4. This pathway is essential for PI3Ks to modulate oxidative stress resistance of nerve cells and insulin-induced growth in fibroblasts. Moreover, the pathway is active in human glioblastoma cells. In addition, it is induced in primary cortical neurons in response to robust neuronal activity and in hippocampi from patients with temporal lobe epilepsy.


METHODS
Our findings further extend the concepts of how growth factors and PI3Ks induce neuroprotection and cell growth by adding a new branch to the signaling network downstream of GSK-3β, which, ultimately, leads to the induction of the cystine/glutamate antiporter system xc(-). Importantly, the induction of this pathway by neuronal activity and in epileptic hippocampi points to a potential role in epilepsy.


CONCLUSIONS
PI3K-regulated system xc(-) activity is not only involved in the stress resistance of neuronal cells and in cell growth by increasing the cysteine supply and glutathione synthesis, but also plays a role in the pathophysiology of tumor- and non-tumor-associated epilepsy by up-regulating extracellular cerebral glutamate.
1 Department of Neurology, Ulm University , Ulm, Germany .
Jan
J
Lewerenz
Paul
P
Baxter
Rebecca
R
Kassubek
Philipp
P
Albrecht
Joeri
J
Van Liefferinge
Mike-Andrew
MA
Westhoff
Marc-Eric
ME
Halatsch
Georg
G
Karpel-Massler
Paul J
PJ
Meakin
John D
JD
Hayes
Eleonora
E
Aronica
Ilse
I
Smolders
Albert C
AC
Ludolph
Axel
A
Methner
Marcus
M
Conrad
Ann
A
Massie
Giles E
GE
Hardingham
Pamela
P
Maher
D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D002460:Cell Line; D004827:Epilepsy / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D014411:Neoplastic Stem Cells; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology*
D027182:Amino Acid Transport System y+; D015852:Eukaryotic Initiation Factor-2; D018696:Neuroprotective Agents; C118895:SLC7A11 protein, human; D051701:Activating Transcription Factor 4; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3