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Cytoplasmic TRADD confers a worse prognosis in glioblastoma.

ABSTRACT: Tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein (TRADD) is an important adaptor in TNFR1 signaling and has an essential role in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) activation and survival signaling. Increased expression of TRADD is sufficient to activate NF-?B. Recent studies have highlighted the importance of NF-?B activation as a key pathogenic mechanism in glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults.We examined the expression of TRADD by immunohistochemistry (IHC) and find that TRADD is commonly expressed at high levels in GBM and is detected in both cytoplasmic and nuclear distribution. Cytoplasmic IHC TRADD scoring is significantly associated with worse progression-free survival (PFS) both in univariate and multivariate analysis but is not associated with overall survival (n = 43 GBMs). PFS is a marker for responsiveness to treatment. We propose that TRADD-mediated NF-?B activation confers chemoresistance and thus a worse PFS in GBM. Consistent with the effect on PFS, silencing TRADD in glioma cells results in decreased NF-?B activity, decreased proliferation of cells, and increased sensitivity to temozolomide. TRADD expression is common in glioma-initiating cells. Importantly, silencing TRADD in GBM-initiating stem cell cultures results in decreased viability of stem cells, suggesting that TRADD may be required for maintenance of GBM stem cell populations. Thus, our study suggests that increased expression of cytoplasmic TRADD is both an important biomarker and a key driver of NF-?B activation in GBM and supports an oncogenic role for TRADD in GBM.

SUBMITTER: Chakraborty S

PROVIDER: S-EPMC3730041 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Cytoplasmic TRADD confers a worse prognosis in glioblastoma.

Chakraborty Sharmistha S Li Li L Tang Hao H Xie Yang Y Puliyappadamba Vineshkumar Thidil VT Raisanen Jack J Burma Sandeep S Boothman David A DA Cochran Brent B Wu Julian J Habib Amyn A AA

Neoplasia (New York, N.Y.) 20130801 8

Tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein (TRADD) is an important adaptor in TNFR1 signaling and has an essential role in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and survival signaling. Increased expression of TRADD is sufficient to activate NF-κB. Recent studies have highlighted the importance of NF-κB activation as a key pathogenic mechanism in glioblastoma multiforme (GBM), the most common primary malignant brain tumor i ...[more]

PMID: 23908590

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Project description:Mutation of the isocitrate dehydrogenase (IDH) gene is regarded a novel indicator for the prognosis of patients with glioma. However, the role of the IDH1 gene mutations in carcinogenesis and the mechanisms underlying their function in glioblastoma multiforme (GBM) remain unknown. The present study aimed to determine whether the association of RLIP76 with the different IDH1 mutational status could serve as a putative biomarker for improving disease prognosis. Quantitative PCR, western blotting and immunohistochemical staining assays were used to investigate the expression levels of RLIP76 in 124 patients with GBM with different IDH1 mutational status. In addition, the association between RLIP76 expression, IDH1 mutational status and clinicopathological characteristics was investigated. The effects of RLIP76 expression and IDH1 mutational status on cell proliferation, cell apoptosis, and cell signaling were examined by Cell Counting Kit‑8, flow cytometry and western blot assays, respectively. The data demonstrated that IDH1 wild‑type (IDH1Wt) patients with low RLIP76 expression exhibited improved overall and progression‑free survival. This effect was not observed in patients with IDH1 mutant (IDH1Mut) GBM. In vitro assays demonstrated that knockdown of IDH1 or overexpression of the IDH1 R132H mutation suppressed cell proliferation and promoted cell apoptosis in U87 glioma cells. Mechanistic studies further indicated that although the IDH1 R132H mutant phenotype exhibited similar antitumor effects on GBM cells as those observed with the IDH1 knockdown, it acted via a different mechanism with regard to the regulation of the apoptosis signaling pathway. IDH1 R132H mutant cells promoted p53‑induced apoptosis, while the IDH1 knockdown inhibited the RLIP76‑dependent apoptotic pathway in glioma cells. The findings of the present study provided insight to the contribution of IDH1 mutation in the development of GBM and indicated that RLIP76 may be considered as a prognostic biomarker of IDH1Wt GBM.

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Cytoplasmic TRADD confers a worse prognosis in glioblastoma.

Publications

Cytoplasmic TRADD confers a worse prognosis in glioblastoma.

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