TY - JOUR
T1 - Cytoplasmic TRADD confers a worse prognosis in glioblastoma
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.
N1 - Funding Information:
Address all correspondence to: Amyn A. Habib, MD, University of Texas Southwestern Medical Center, North Texas VA Healthcare System, Mail Code 151, 4500 South Lancaster Road, Dallas, TX 75216. E-mail: [email protected] 1This work was supported in part by National Institutes of Health (NIH) grant R01NS062080 to A.A.H. and by R01 CA139217 to D.A.B. S.B. is supported by grants from the NIH (R01 CA149461), National Aeronautics and Space Administration (NNX13AI13G), and the Cancer Prevention and Research Institute of Texas (RP100644). 2This article refers to supplementary material, which is designated by Table W1 and is available online at www.neoplasia.com. Received 5 March 2013; Revised 26 April 2013; Accepted 29 April 2013 Copyright © 2013 Neoplasia Press, Inc. All rights reserved 1522-8002/13/$25.00 DOI 10.1593/neo.13608
PY - 2013/8
Y1 - 2013/8
N2 - 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.
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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U2 - 10.1593/neo.13608
DO - 10.1593/neo.13608
M3 - Article
C2 - 23908590
AN - SCOPUS:84881060176
SN - 1522-8002
VL - 15
SP - 888
EP - 897
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 8
ER -