title: 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-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.
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Hao
authors.initials: H
authors.lastname: Tang
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.forename: Vineshkumar Thidil
authors.initials: VT
authors.lastname: Puliyappadamba
authors.forename: Jack
authors.initials: J
authors.lastname: Raisanen
authors.forename: Sandeep
authors.initials: S
authors.lastname: Burma
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
authors.forename: Brent
authors.initials: B
authors.lastname: Cochran
authors.forename: Julian
authors.initials: J
authors.lastname: Wu
authors.forename: Amyn A
authors.initials: AA
authors.lastname: Habib
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D034622:RNA Interference; D053199:TNF Receptor-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D000077204:Temozolomide; D046888:Tissue Array Analysis
chemical_list: D018906:Antineoplastic Agents, Alkylating; D016328:NF-kappa B; D053199:TNF Receptor-Associated Death Domain Protein; D003606:Dacarbazine; D000077204:Temozolomide
references.citation: Cell. 1996 Jan 26;84(2):299-308
references.pmid: 8565075
references.citation: Neoplasia. 2010 Sep;12(9):675-84
references.pmid: 20824044
references.citation: Cancer Res. 2009 Apr 1;69(7):2809-16
references.pmid: 19339267
references.citation: Nature. 2010 Jan 21;463(7279):318-25
references.pmid: 20032975
references.citation: Cell Cycle. 2012 Mar 1;11(5):871-6
references.pmid: 22333735
references.citation: PLoS One. 2009 Nov 13;4(11):e7752
references.pmid: 19915670
references.citation: Nat Rev Cancer. 2002 Apr;2(4):301-10
references.pmid: 12001991
references.citation: Cell. 2003 Jul 25;114(2):181-90
references.pmid: 12887920
references.citation: Cytogenet Cell Genet. 2001;92(3-4):347-8
references.pmid: 11435712
references.citation: Biochem Pharmacol. 2006 Oct 30;72(9):1142-52
references.pmid: 16956585
references.citation: Oncogene. 2000 Nov 16;19(48):5498-506
references.pmid: 11114727
references.citation: Mol Cell Biol. 1999 Apr;19(4):2690-8
references.pmid: 10082535
references.citation: Neoplasia. 2012 Mar;14(3):178-89
references.pmid: 22496618
references.citation: J Clin Invest. 2004 Aug;114(4):569-81
references.pmid: 15314694
references.citation: Nat Rev Neurosci. 2004 Oct;5(10):782-92
references.pmid: 15378038
references.citation: Cancer Cell. 2006 May;9(5):391-403
references.pmid: 16697959
references.citation: J Cell Biol. 2002 Jun 10;157(6):975-84
references.pmid: 12045187
references.citation: Cancer Cell. 2010 Jan 19;17(1):98-110
references.pmid: 20129251
references.citation: Nat Immunol. 2004 Feb;5(2):199-207
references.pmid: 14730360
references.citation: Science. 2008 Sep 26;321(5897):1807-12
references.pmid: 18772396
references.citation: J Biol Chem. 2001 Mar 23;276(12):8865-74
references.pmid: 11116146
references.citation: Oncogene. 1998 Apr 23;16(16):2095-102
references.pmid: 9572490
references.citation: Oncogene. 1999 Nov 22;18(49):6853-66
references.pmid: 10602461
references.citation: Nat Cell Biol. 2012 May 06;14(6):625-33
references.pmid: 22561347
references.citation: Cancer Res. 2009 May 15;69(10):4107-11
references.pmid: 19435890
references.citation: Nature. 2004 Nov 18;432(7015):396-401
references.pmid: 15549107
references.citation: PLoS Biol. 2010 Feb 23;8(2):e1000319
references.pmid: 20186265
references.citation: Neoplasia. 2013 Apr;15(4):409-20
references.pmid: 23555186
references.citation: Cancer Cell. 2004 Sep;6(3):203-8
references.pmid: 15380510
references.citation: Nat Rev Immunol. 2003 Sep;3(9):745-56
references.pmid: 12949498
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12429-34
references.pmid: 18719121
references.citation: Neuro Oncol. 1999 Jan;1(1):14-25
references.pmid: 11554386
references.citation: Neoplasia. 2012 Dec;14(12):1097-101
references.pmid: 23308042
references.citation: Cell Growth Differ. 1999 Dec;10(12):819-28
references.pmid: 10616907
references.citation: J Clin Invest. 2012 Oct;122(10):3473-5
references.pmid: 23006324
references.citation: Oncologist. 2006 Feb;11(2):152-64
references.pmid: 16476836
references.citation: Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8542-7
references.pmid: 10900013
references.citation: EMBO J. 2006 Aug 23;25(16):3801-12
references.pmid: 16902410
references.citation: Nature. 2008 Oct 23;455(7216):1061-8
references.pmid: 18772890
references.citation: N Engl J Med. 2011 Feb 17;364(7):627-37
references.pmid: 21175304
references.citation: Cell. 2001 Dec 14;107(6):763-75
references.pmid: 11747812
references.citation: Cancer Cell. 2006 Mar;9(3):157-73
references.pmid: 16530701
references.citation: Mol Biol Cell. 2003 Feb;14(2):585-99
references.pmid: 12589056
references.citation: Oncogene. 2011 Aug 11;30(32):3537-48
references.pmid: 21423202
references.citation: Cell. 1995 May 19;81(4):495-504
references.pmid: 7758105
references.citation: Cell. 2006 Oct 6;127(1):157-70
references.pmid: 17018283
references.citation: Nat Rev Mol Cell Biol. 2007 Jan;8(1):49-62
references.pmid: 17183360