title: Activation of death-associated protein kinase in human peritumoral tissue: A potential therapeutic target.
abstract: To further understand the molecular mechanisms of N-methyl-D-aspartate receptor 2B (NR2B) phosphorylation and its contribution to glioma-related seizures, we investigated the expression of death-associated protein kinase-1 (DAPK1), which is a kinase known to phosphorylate NR2B at S1303 in glioma and peritumoral tissue. The molecular mechanisms leading to glioma-associated seizures are poorly understood. We recently discovered that NR2B is phosphorylated at S1303 in glioma peritumoral tissue. NR2B is an excitatory glutamate receptor, suggesting that glutamate released from glioma tumor cells may excite the neurons in the peritumoral tissue and contribute to glioma-associated epileptogenesis. DAPK1 levels were assessed in an intracranial mouse model of human glioma and in primary patient peritumoral and glioma tissues using immunohistochemistry. DAPK1 is highly expressed in the peritumoral region, but is poorly expressed in glioma tissues in both a mouse model of human glioma and in the primary patient glioma. In our previous report, we found that NR2B is also highly phosphorylated in the same region. Upregulation of DAPK1 in the peritumoral tissues suggests that DAPK1 can phosphorylate NR2B, increase its excitability, lead to glioma-induced seizures, and could potentially be an important therapeutic target. Furthermore, the xenograft model offers an opportunity to develop and test therapeutic approaches that can block DAPK1 activity in vivo.
authors.affiliation: Department of Neurological Surgery, Indiana University, 355 West 16th Street, Suite 5100, Indianapolis, IN 46202, USA; Stark Neuroscience Research Center, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Herman B. Wells Center for Pediatric Research, Riley Hospital for Children, Indiana University Health, Indianapolis, IN, USA; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA; Simon Cancer Center, Indiana University, Indianapolis, IN, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Herman B. Wells Center for Pediatric Research, Riley Hospital for Children, Indiana University Health, Indianapolis, IN, USA; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA; Simon Cancer Center, Indiana University, Indianapolis, IN, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Pollok
authors.affiliation: Department of Neurological Surgery, Indiana University, 355 West 16th Street, Suite 5100, Indianapolis, IN 46202, USA; Stark Neuroscience Research Center, Indiana University School of Medicine, Indianapolis, IN, USA; Goodman Campbell Brain and Spine, Indianapolis, IN, USA.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Neurological Surgery, Indiana University, 355 West 16th Street, Suite 5100, Indianapolis, IN 46202, USA; Simon Cancer Center, Indiana University, Indianapolis, IN, USA; Goodman Campbell Brain and Spine, Indianapolis, IN, USA. Electronic address: acohenmd@gmail.com.
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Cohen-Gadol
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases / Q000096:biosynthesis*; D016503:Drug Delivery Systems / Q000639:trends; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis
chemical_list: C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases
keywords: Death associated protein kinase 1; Glioblastoma multiforme; Peritumoral seizures