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-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 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-κB 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-κB 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-κB activation in GBM and supports an oncogenic role for TRADD in GBM.

Original languageEnglish (US)
Pages (from-to)888-897
Number of pages10
JournalNeoplasia (United States)
Volume15
Issue number8
DOIs
StatePublished - Aug 2013

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Receptors, Tumor Necrosis Factor, Type I
Glioblastoma
Proteins
Disease-Free Survival
Stem Cells
Tumor Necrosis Factor Receptors
temozolomide
Glioma
Death Domain
Immunohistochemistry
Brain Neoplasms

ASJC Scopus subject areas

  • Cancer Research

Cite this

Cytoplasmic TRADD confers a worse prognosis in glioblastoma. / Chakraborty, Sharmistha; Li, Li; Tang, Hao; Xie, Yang; Puliyappadamba, Vineshkumar Thidil; Raisanen, Jack; Burma, Sandeep; Boothman, David A.; Cochran, Brent; Wu, Julian; Habib, Amyn A.

In: Neoplasia (United States), Vol. 15, No. 8, 08.2013, p. 888-897.

Research output: Contribution to journalArticle

Chakraborty, S, Li, L, Tang, H, Xie, Y, Puliyappadamba, VT, Raisanen, J, Burma, S, Boothman, DA, Cochran, B, Wu, J & Habib, AA 2013, 'Cytoplasmic TRADD confers a worse prognosis in glioblastoma', Neoplasia (United States), vol. 15, no. 8, pp. 888-897. https://doi.org/10.1593/neo.13608
Chakraborty, Sharmistha ; Li, Li ; Tang, Hao ; Xie, Yang ; Puliyappadamba, Vineshkumar Thidil ; Raisanen, Jack ; Burma, Sandeep ; Boothman, David A. ; Cochran, Brent ; Wu, Julian ; Habib, Amyn A. / Cytoplasmic TRADD confers a worse prognosis in glioblastoma. In: Neoplasia (United States). 2013 ; Vol. 15, No. 8. pp. 888-897.
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AU - Chakraborty, Sharmistha

AU - Li, Li

AU - Tang, Hao

AU - Xie, Yang

AU - Puliyappadamba, Vineshkumar Thidil

AU - Raisanen, Jack

AU - Burma, Sandeep

AU - Boothman, David A.

AU - Cochran, Brent

AU - Wu, Julian

AU - Habib, Amyn A.

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AB - 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 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-κB 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-κB 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-κB activation in GBM and supports an oncogenic role for TRADD in GBM.

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