Phosphoinositide 3-kinases upregulate system xc- via eukaryotic initiation factor 2α and activating transcription factor 4-A pathway active in glioblastomas and epilepsy

Jan Lewerenz (Lead / Corresponding author), Paul Baxter, Rebecca Kassubek, Philipp Albrecht, Joeri Van Liefferinge, Mike-Andrew Westhoff, Marc-Eric Halatsch, Georg Karpel-Massler, Paul J. Meakin, John D. Hayes, Eleonora Aronica, Ilse Smolders, Albert C. Ludolph, Axel Methner, Marcus Conrad, Ann Massie, Giles E. Hardingham, Pamela Maher

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    43 Citations (Scopus)

    Abstract

    Aims: 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 3ß (GSK-3ß) inhibition, general control non-derepressible-2-mediated eukaryotic initiation factor 2a 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. Innovation: 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-3ß, 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. Conclusion: 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.

    Original languageEnglish
    Pages (from-to)2907-2922
    Number of pages16
    JournalAntioxidants & Redox Signaling
    Volume20
    Issue number18
    DOIs
    Publication statusPublished - 28 May 2014

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