Identification of molecular alterations and signaling abnormalities that initiate and maintain the malignant phenotype in glioblastoma (GBM) is a key step in designing treatment. The NF-?B and PI3K-Akt pathways are deregulated in GBM and likely to play key roles in the pathogenesis of GBM and in resistance to treatment. NF-?B activation is a hallmark of inflammation. In this proposal, we aim to characterize the role of the death domain containing kinase receptor interacting protein (RIP, RIP1), in the biology of GBM. RIP1 activates both the NF-?B and PI3K-Akt pathways in glioma cells. In addition, RIP1 negatively regulates two key tumor suppressor signaling networks, the PTEN and the p53 pathways. RIP1 levels are increased in up to 30% of GBMs but not in Grade II-III gliomas. Furthermore, RIP1 expression confers a worse prognosis in GBM, overexpressing RIP1 induces proliferation of glioma cells and silencing RIP1 inhibits proliferation of glioma cells in an animal model of glioma. The central hypothesis of this proposal is that RIP1 plays a key role in the pathogenesis of GBM and resistance to treatment by regulating key signaling pathways in tumor cells. The broad goal of this proposal is to demonstrate experimentally that RIP1 promotes the malignant phenotype of GBM.
In Specific Aim 1, we will explore the mechanistic relationships coupling RIP1 to the proliferation of glioma cells and identify RIP1 specific effector mechanisms influencing proliferation and resistance to chemotherapy in glioma cells.
In Specific Aim 2, we will determine the mechanisms and biological significance of RIP1 mediated inhibition of tumor suppressor signaling.
In Specific Aim 3 we will benchmark the effect of RIP1 expression in glioma cells using an orthotopic animal model. This study may provide useful insights into the role of inflammation in GBM and help in the design of more effective treatments targeting inflammatory signaling pathways in GBM.
RIP1, a protein involved in inflammation, is highly expressed in GBM and confers a poor prognosis. We investigate the mechanisms used by RIP1 to promote growth of malignant glioma. Improved understanding of RIP1 in glioma may lead to design of more rational targeted treatment.
|Hatanpaa, Kimmo J; Hu, Tianshen; Vemireddy, Vamsidhara et al. (2014) High expression of the stem cell marker nestin is an adverse prognostic factor in WHO grade II-III astrocytomas and oligoastrocytomas. J Neurooncol 117:183-9|
|Li, L; Chakraborty, S; Yang, C-R et al. (2014) An EGFR wild type-EGFRvIII-HB-EGF feed-forward loop regulates the activation of EGFRvIII. Oncogene 33:4253-64|
|Hatanpaa, Kimmo J; Raisanen, Jack M; Herndon, Emily et al. (2014) Hippocampal sclerosis in dementia, epilepsy, and ischemic injury: differential vulnerability of hippocampal subfields. J Neuropathol Exp Neurol 73:136-42|
|Chakraborty, Sharmistha; Li, Li; Puliyappadamba, Vineshkumar Thidil et al. (2014) Constitutive and ligand-induced EGFR signalling triggers distinct and mutually exclusive downstream signalling networks. Nat Commun 5:5811|
|Gil del Alcazar, Carlos Rodrigo; Hardebeck, Molly Catherine; Mukherjee, Bipasha et al. (2014) Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma. Clin Cancer Res 20:1235-48|
|Saddoughi, Sahar A; Gencer, Salih; Peterson, Yuri K et al. (2013) Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis. EMBO Mol Med 5:105-21|
|Chakraborty, Sharmistha; Li, Li; Tang, Hao et al. (2013) Cytoplasmic TRADD confers a worse prognosis in glioblastoma. Neoplasia 15:888-97|
|Puliyappadamba, Vineshkumar Thidil; Chakraborty, Sharmistha; Chauncey, Sandili S et al. (2013) Opposing effect of EGFRWT on EGFRvIII-mediated NF-*B activation with RIP1 as a cell death switch. Cell Rep 4:764-75|
|Camacho, Cristel V; Mukherjee, Bipasha; McEllin, Brian et al. (2010) Loss of p15/Ink4b accompanies tumorigenesis triggered by complex DNA double-strand breaks. Carcinogenesis 31:1889-96|
|Hatanpaa, Kimmo J; Burma, Sandeep; Zhao, Dawen et al. (2010) Epidermal growth factor receptor in glioma: signal transduction, neuropathology, imaging, and radioresistance. Neoplasia 12:675-84|