title: Increased glutamate uptake in astrocytes via propentofylline results in increased tumor cell apoptosis using the CNS-1 glioma model.
abstract: Glioblastoma multiform is one of the most common and aggressive primary brain tumors in adults. High glutamate levels are thought to contribute to glioma growth. While research has focused on understanding glutamate signaling in glioma cells, little is known about the role of glutamate between glioma and astrocyte interactions. To study the relationship between astrocytes and tumor cells, the CNS-1 rodent glioma cell line was used. We hypothesized increased glutamate uptake by astrocytes would negatively affect CNS-1 cell growth. Primary rodent astrocytes and CNS-1 cells were co-cultured for 7 days in a Boyden chamber in the presence of 5 mM glutamate. Cells were treated with propentofylline, an atypical synthetic methylxanthine known to increase glutamate transporter expression in astrocytes. Our results indicate astrocytes can increase glutamate uptake through the GLT-1 transporter, leading to less glutamate available for CNS-1 cells, ultimately resulting in increased CNS-1 cell apoptosis. These data suggest that astrocytes in the tumor microenvironment can be targeted by the drug, propentofylline, affecting tumor cell growth.
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. valerie.l.jacobs.gr@dartmouth.edu
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Jacobs
authors.forename: Joyce A
authors.initials: JA
authors.lastname: De Leo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D027342:Excitatory Amino Acid Transporter 2; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000473:pathology; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D017304:Annexin A5; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; C493397:SLC1A2 protein, human; D014970:Xanthines; D018698:Glutamic Acid; C032114:propentofylline