ASTROCYTE-ELEVATED GENE-1 PROTECTS HUMAN ASTROCYTES FROM OXIDATIVE STRESS-INDUCED CELL DEATH: A POTENTIAL SURVIVAL MECHANISM IN HAND AND GLIOMA PATHOGENESIS

Purpose: Astrocyte elevated gene-1 (AEG-1), a novel human immunodeficiency virus (HIV-1)- and tumor necrosis factor-ɑ-inducible oncogene, has generated significant interest in the field of cancer research as a therapeutic target for many metastatic cancers. However, little is known of its role in astrocyte behavior and function during HIV-1 central nervous system (CNS) infection, and whether it contributes towards the development of HIV-1-associated neurocognitive disorders. Based on its putative role in cancer as a chemotherapy resistance marker, here, we investigated whether AEG-1 induction in astrocytes alters their responses to oxidative stress, a hallmark feature of neuroinflammatory disorders. Methods: Oxidative stress induced changes in AEG-1 mRNA and protein were assessed by real-time PCR, immunoblotting and confocal microscopy. Astrocyte responses to oxidative stress were assayed by measuring the changes in catalase activity, protein carbonylation and glutathion production. AEG-1 mediated protection against oxidative damage was assessed by measuring the anti-oxidant mechanisms upon AEG-1 knockdown. Results: Analysis of AEG-1 mRNA levels in an aging cohort of HIV-1 seropositive and seronegative human brain tissues showed a significant positive correlation to aging. A dose-dependent increase in AEG-1 astrocyte nucleolar localization was noted following treatment with oxidative stress stimuli, hydrogen peroxide, as assayed by immunostaining and confocal microscopy. Cell death and cell survival assays to quantify apoptotic nuclei, mitochondrial depolarization and activity, and cell membrane permeability demonstrated a novel role of AEG-1 in protecting astrocytes from oxidative-stress-induced damage. Conclusions: Together, findings from this study suggest that AEG-1 may play a role in protecting astrocytes from oxidative stress-induced DNA damage, a plausible mechanism of astrocyte survival during HIV-1 CNS infection-induced toxicity.