A formidable challenge in the treatment of primary and metastatic brain cancers, especially in children, is the long-term neurocognitive deficiencies resulting from cranial irradiation (IR)-induced hippocampal neuronal apoptosis. Our laboratory has discovered a novel functional connection between the metabolic kinase GSK3? and the Non- homologous End-joining (NHEJ) pathway that repair DNA double-strand breaks (DSBs). Furthermore, our preliminary data revealed that the NHEJ mediator 53BP1 is directly phosphorylated by GSK3?;meanwhile, increased expression of the classic GSK3? substrate ?-catenin is associated with enhanced repair of IR-induced DSBs and survival in hippocampal neurons. Thus, we hypothesize that GSK3? regulates NHEJ-mediated repair of DSBs and determines neuron cytotoxicity following IR via suppression of 53BP1 and ?-catenin function. In addition, tumor cells which contain abnormal GSK3 ? activity will not exhibit GSK3?-mediated protection from IR-induced cytotoxicity. A series of in vitro and in vivo experiments are proposed to test our hypotheses:
Aim 1 will identify the GSK3 ? phosphorylation sites in 53BP1 and determine whether GSK3 ? -specific phosphorylation direct 53BP1 function in NHEJ and in survival of irradiated hippocampal neurons.
Aim 2 will determine whether GSK3 ? regulates 53BP1 through suppressing ? - catenin that may promote NHEJ activity by increasing 53BP1 transcription, or by directly interacts with 53BP1.
Aim 3 will determine if abnormal GSK3 ? activity determine brain tumor cell resistance to the prophylactic GSK3 ? -inhibition mediated protection from radiation induced cytotoxicity.
In an effort to decrease neurotoxicity and improve patient quality of life, pharmacologic agents which exhibit neuroprotective effects are being rigorously investigated. Thus, the goal of this proposal is to determine the mechanisms of action that protect neurons from irradiation-induced hippocampal neuronal apoptosis with a view toward prevention of neurocognitive toxicity from cranial IR.
|Desouki, Mohamed Mokhtar; Doubinskaia, Irina; Gius, David et al. (2014) Decreased mitochondrial SIRT3 expression is a potential molecular biomarker associated with poor outcome in breast cancer. Hum Pathol 45:1071-7|
|Wang, Tong; Wentz, Sabrina C; Ausborn, Natalie L et al. (2013) Pattern of breast cancer susceptibility gene 1 expression is a potential prognostic biomarker in resectable pancreatic ductal adenocarcinoma. Pancreas 42:977-82|