title: SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma.
abstract: Glioma is the most common malignant primary brain tumor. Its rapid growth is aided by tumor-mediated glutamate release, creating peritumoral excitotoxic cell death and vacating space for tumor expansion. Glioma glutamate release may also be responsible for seizures, which complicate the clinical course for many patients and are often the presenting symptom. A hypothesized glutamate release pathway is the cystine/glutamate transporter System xc (-) (SXC), responsible for the cellular synthesis of glutathione (GSH). However, the relationship of SXC-mediated glutamate release, seizures, and tumor growth remains unclear. Probing expression of SLC7A11/xCT, the catalytic subunit of SXC, in patient and mouse-propagated tissues, we found that ~50% of patient tumors have elevated SLC7A11 expression. Compared with tumors lacking this transporter, in vivo propagated and intracranially implanted SLC7A11-expressing tumors grew faster, produced pronounced peritumoral glutamate excitotoxicity, induced seizures, and shortened overall survival. In agreement with animal data, increased SLC7A11 expression predicted shorter patient survival according to genomic data in the REMBRANDT (National Institutes of Health Repository for Molecular Brain Neoplasia Data) database. In a clinical pilot study, we used magnetic resonance spectroscopy to determine SXC-mediated glutamate release by measuring acute changes in glutamate after administration of the U.S. Food and Drug Administration-approved SXC inhibitor, sulfasalazine (SAS). In nine glioma patients with biopsy-confirmed SXC expression, we found that expression positively correlates with glutamate release, which is acutely inhibited with oral SAS. These data suggest that SXC is the major pathway for glutamate release from gliomas and that SLC7A11 expression predicts accelerated growth and tumor-associated seizures.
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Robert
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Buckingham
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Campbell
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Robel
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Holt
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Toyin
authors.initials: T
authors.lastname: Ogunrinu-Babarinde
authors.affiliation: Division of Neuro-oncology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Paula P
authors.initials: PP
authors.lastname: Warren
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: White
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Reid
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Eschbacher
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Berens
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Adrienne C
authors.initials: AC
authors.lastname: Lahti
authors.affiliation: Division of Neuro-oncology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Louis B
authors.initials: LB
authors.lastname: Nabors
authors.affiliation: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. sontheimer@uab.edu.
authors.forename: Harald
authors.initials: H
authors.lastname: Sontheimer
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D004487:Edema / Q000473:pathology; D023281:Genomics; D005910:Glioma / Q000145:classification / Q000150:complications* / Q000378:metabolism*; D005971:Glutamates / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D012640:Seizures / Q000150:complications* / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D027182:Amino Acid Transport System y+; D005971:Glutamates; D009498:Neurotoxins; C118895:SLC7A11 protein, human