Glioblastoma is the most common and lethal brain tumor for which there is no curative treatment. In search for new therapeutic agents, we have shown that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) can induce programmed cell death (apoptosis) in glioblastoma cells and it may offer a new hope for a cure. TRAIL has therefore entered the clinical trials for cancer treatment. Earlier reports from the trials, unfortunately, have shown a limited antitumor activity and indicated that the majority of human cancers including glioblastomas are resistant to TRAIL. The current research proposal will therefore examine the molecular basis of TRAIL resistance in glioblastomas. TRAIL-induced apoptosis occurs through binding to the death receptor DR5 and the recruitment of caspase-8 to DR5 for the formation of DISC (death-inducing signaling complex). In the DISC, caspase-8 forms dimers and then becomes proteolytically active in the initiation of the programmed cell death. Our Preliminary Studies show that the caspase-8 dimerization and cleavage are inhibited in TRAIL-resistant glioblastoma cells. In search for the mechanism in the caspase-8 inhibition, we have discovered a DR5-associated proteins complex that is formed prior to TRAIL treatment and we therefore name the PLAC (pre-ligand assembly complex). Our Preliminary Studies show that the PLAC components define the subsequent formation of the DISC and thus control caspase-8 dimerization and cleavage. Specifically, the Preliminary Studies identify RIP (receptor-interacting protein) and A20, a RIP ubiquitin enzyme in the PLAC and show that TRAIL treatment leads to the RIP ubiquitination and caspase-8 inhibition during the TRAIL-induced formation from the PLAC to the DISC. We therefore hypothesize that A20-mediated RIP ubiquitination inhibits caspase-8 dimerization and cleavage. To test this hypothesis, we will define the role of A20 as the RIP ubiquitin ligase, determine the polyubiquitin chain attached to RIP and identify the polyubiquitin binding domain on caspase-8. In addition, we will generate mouse xenografts and primary cultures from patient's glioblastomas and determine whether A20 is overexpressed in the tumors and thus defines the TRAIL resistance in the tumors. Upon the completion, this study will identify A20 as a therapeutic target and thus benefit human health by developing the combination therapy that can target A20 inhibitory mechanisms to overcome the tumor resistance to TRAIL treatment.

Public Health Relevance

The objective of this proposal is to develop TRAIL as a therapeutic agent in treating of glioblastomas. This proposal will yield significant results, with immediate and long term impact on clinical treatment of human glioblastoma, one of the most deadly human cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Arya, Suresh
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Emory University
Schools of Medicine
United States
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Bellail, Anita C; Olson, Jeffrey J; Hao, Chunhai (2014) SUMO1 modification stabilizes CDK6 protein and drives the cell cycle and glioblastoma progression. Nat Commun 5:4234
Wang, Quan; Wei, Feng; Li, Chunsheng et al. (2013) Combination of mTOR and EGFR kinase inhibitors blocks mTORC1 and mTORC2 kinase activity and suppresses the progression of colorectal carcinoma. PLoS One 8:e73175
Wang, Quan; Wei, Feng; Lv, Guoyue et al. (2013) The association of TP53 mutations with the resistance of colorectal carcinoma to the insulin-like growth factor-1 receptor inhibitor picropodophyllin. BMC Cancer 13:521
Bellail, Anita C; Olson, Jeffrey J; Yang, Xiaolu et al. (2012) A20 ubiquitin ligase-mediated polyubiquitination of RIP1 inhibits caspase-8 cleavage and TRAIL-induced apoptosis in glioblastoma. Cancer Discov 2:140-55
Wei, Feng; Liu, Yan; Bellail, Anita C et al. (2012) K-Ras mutation-mediated IGF-1-induced feedback ERK activation contributes to the rapalog resistance in pancreatic ductal adenocarcinomas. Cancer Lett 322:58-69
Bellail, Anita C; Hao, Chunhai (2012) The roadmap of TRAIL apoptotic pathway-targeted cancer therapies: What is next? Expert Rev Anticancer Ther 12:547-9
Ding, Lijuan; Yuan, Changji; Wei, Feng et al. (2011) Cisplatin restores TRAIL apoptotic pathway in glioblastoma-derived stem cells through up-regulation of DR5 and down-regulation of c-FLIP. Cancer Invest 29:511-20
Qi, Ling; Bellail, Anita C; Rossi, Michael R et al. (2011) Heterogeneity of primary glioblastoma cells in the expression of caspase-8 and the response to TRAIL-induced apoptosis. Apoptosis 16:1150-64
Bellail, Anita C; Tse, Margaret C L; Song, Jin H et al. (2010) DR5-mediated DISC controls caspase-8 cleavage and initiation of apoptosis in human glioblastomas. J Cell Mol Med 14:1303-17