Malignant gliomas are diffusively infiltrative and remain among the deadliest of all cancers. NF-?B is a transcription factor that mediates cell growth, migration and invasion, angiogenesis and resistance to apoptosis. In gliomas, NF-?B is constitutively activated and is inversely correlated with patient prognosis. At present, it is not clear how NF-?B becomes activated, or why NF-?B remains activated in gliomas. We found that NF-?B is constitutively activated and correlates with increased levels of genes that promote glioma growth, invasion and angiogenesis. ING4, a tumor suppressor, is absent or mutated in gliomas. We have determined that ING4 attenuates nuclear NF-?B function. In particular, ING4 is critical for discriminately identifying and binding those NF-?B molecules that are currently or have recently induced gene expression. Once bound to NF-?B, ING4 toggles the activity of NF-?B from active to inactive. Objective/Hypothesis: We hypothesize that in gliomas, NF-?B becomes inevitably activated and induces the expression of genes that mediate glioma growth, angiogenesis, invasion and resistance to apoptosis. Therefore, strategies that target NF-?B or methods to reduce NF-?B expression should reduce glioma growth, invasion and apoptotic resistance. We also hypothesize that the absence of ING4 enables already activated NF-?B to persistently induce the expression of genes that mediate cell growth, migration and invasion, angiogenesis and resistance to apoptotic stimuli. Therefore, strategies to restore ING4 expression or the functions mediated by ING4 should reduce facets of glioma behavior.
Specific Aims : (1) Elucidate the role of activated NF-?B in regulating glioma growth, invasion and apoptotic resistance;(2) Characterize the role of ING4 in regulating NF-?B activity, and understand the consequence(s) of loss of ING4 function during glioma formation and progression;and (3) Clarify the roles of activated NF-?B and ING4 loss on brain tumor growth, invasion, angiogenesis and apoptotic resistance in vivo. Study Design: Herein, we propose to use human glioma cell lines that inducibly regulate endogenous NF-?B protein expression, or endogenous and exogenous ING4 expression. With these cell lines, we will elucidate the role of NF-?B p65 in activating the expression of genes that mediate facets of glioma behavior. Additionally, we will determine how ING4 regulates the activity of NF-?B to reduce gene expression, and inhibit glioma cell growth, invasion, migration, angiogenesis and apoptotic resistance. These studies will provide valuable information about how the absence or presence of ING4 may enable tumors to modulate their behavior and acquire chemo- and/or radioresistance. Finally, we will use the information provided above to transition into studies that allow us to assess in vivo how the presence or absence of NF-?B protein(s) or ING4 affects cell growth, invasion, migration, angiogenesis and apoptotic resistance in the context of gliomas. Ultimately, these studies will allow us to determine how the status of NF-?B and/or ING4 affect the response of gliomas to current therapeutic strategies.
Malignant gliomas are the deadliest tumors of the central nervous system and may result from dysregulated Nuclear Factor-?B (NF-?B). While ING4 can regulate NF-?B, this protein is absent or mutated in human gliomas. We hypothesize that in gliomas, the lack of ING4 protein allows NF-?B to inappropriately promote tumor formation and growth, and herein propose to address the roles of NF-?B and ING4 during the processes of glioma formation and progression.
|Rajbhandari, Rajani; McFarland, Braden C; Patel, Ashish et al. (2015) Loss of tumor suppressive microRNA-31 enhances TRADD/NF-ÎºB signaling in glioblastoma. Oncotarget 6:17805-16|
|Gray, G Kenneth; McFarland, Braden C; Nozell, Susan E et al. (2014) NF-ÎºB and STAT3 in glioblastoma: therapeutic targets coming of age. Expert Rev Neurother 14:1293-306|
|Madanecki, Piotr; Nozell, Susan; Ochocka, Renata et al. (2014) RNAdigest: a web-based tool for the analysis and prediction of structure-specific RNAse digestion results. PLoS One 9:e96759|
|McFarland, Braden C; Gray, G Kenneth; Nozell, Susan E et al. (2013) Activation of the NF-ÎºB pathway by the STAT3 inhibitor JSI-124 in human glioblastoma cells. Mol Cancer Res 11:494-505|
|McFarland, Braden C; Hong, Suk W; Rajbhandari, Rajani et al. (2013) NF-ÎºB-induced IL-6 ensures STAT3 activation and tumor aggressiveness in glioblastoma. PLoS One 8:e78728|
|Park, Keun W; Nozell, Susan E; Benveniste, Etty N (2012) Protective role of STAT3 in NMDA and glutamate-induced neuronal death: negative regulatory effect of SOCS3. PLoS One 7:e50874|
|Xing, Dongqi; Gong, Kaizheng; Feng, Wenguang et al. (2011) O-GlcNAc modification of NFÎºB p65 inhibits TNF-Î±-induced inflammatory mediator expression in rat aortic smooth muscle cells. PLoS One 6:e24021|
|McFarland, Braden C; Ma, Jing-Yuan; Langford, Catherine P et al. (2011) Therapeutic potential of AZD1480 for the treatment of human glioblastoma. Mol Cancer Ther 10:2384-93|
|Zhao, Xueyan; Laver, Travis; Hong, Suk W et al. (2011) An NF-ÎºB p65-cIAP2 link is necessary for mediating resistance to TNF-Î± induced cell death in gliomas. J Neurooncol 102:367-81|