Activation of death-associated protein kinase in human peritumoral tissue: A potential therapeutic target
Xiang Gao1, Haiyan Wang2, Karen E Pollok2
1Department 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.
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.
Insights
Death-associated protein kinase-1 (DAPK1) is upregulated in brain tissue surrounding gliomas, suggesting it phosphorylates N-methyl-D-aspartate receptor 2B (NR2B) and contributes to seizures.
Area of Science:
- Neuroscience
- Oncology
- Molecular Biology
Background:
- Glioma-associated seizures are a common and debilitating complication.
- The molecular mechanisms underlying glioma-induced epileptogenesis are not fully understood.
- N-methyl-D-aspartate receptor 2B (NR2B) phosphorylation at S1303 was recently identified in peritumoral tissue.
Purpose of the Study:
- To investigate the role of death-associated protein kinase-1 (DAPK1) in NR2B phosphorylation and glioma-associated seizures.
- To determine DAPK1 expression levels in glioma and peritumoral tissues.
Main Methods:
- Immunohistochemistry was used to assess DAPK1 expression.
- Studies were conducted in an intracranial mouse model of human glioma and in primary patient tissues.
Main Results:
- DAPK1 was highly expressed in the peritumoral region of both the mouse model and patient tissues.
- DAPK1 expression was low in glioma tissues.
- This correlates with previously observed high NR2B phosphorylation in the peritumoral region.
Conclusions:
- Upregulation of DAPK1 in peritumoral tissue likely contributes to NR2B phosphorylation and glioma-induced seizures.
- DAPK1 represents a potential therapeutic target for managing glioma-associated seizures.
- The developed xenograft model can be used for in vivo therapeutic testing.
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