title: Targeting NF-κB in glioblastoma: A therapeutic approach.
abstract: Glioblastoma multiforme (GBM) is the most common and lethal form of intracranial tumor. We have established a lentivirus-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signature of mesenchymal human GBM. RNA-Seq analysis of these tumors revealed high nuclear factor κB (NF-κB) activation showing enrichment of known NF-κB target genes. Inhibition of NF-κB by either depletion of IκB kinase 2 (IKK2), expression of a IκBαM super repressor, or using a NEMO (NF-κB essential modifier)-binding domain (NBD) peptide in tumor-derived cell lines attenuated tumor proliferation and prolonged mouse survival. Timp1, one of the NF-κB target genes significantly up-regulated in GBM, was identified to play a role in tumor proliferation and growth. Inhibition of NF-κB activity or silencing of Timp1 resulted in slower tumor growth in both mouse and human GBM models. Our results suggest that inhibition of NF-κB activity or targeting of inducible NF-κB genes is an attractive therapeutic approach for GBM.
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.; Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Dinorah
authors.identifier: 0000-0002-6394-9876
authors.initials: D
authors.lastname: Friedmann-Morvinski
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Rajesh
authors.identifier: 0000-0003-4224-3791
authors.initials: R
authors.lastname: Narasimamurthy
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Myskiw
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Soda
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Inder M
authors.initials: IM
authors.lastname: Verma
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000235:genetics*; D010455:Peptides / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D016328:NF-kappa B; D010455:Peptides; D051550:I-kappa B Kinase
keywords: Gliomas; NF-κB inhibitors; TIMP1; Xenografts
references.citation: Cell Death Differ. 2006 May;13(5):785-97
references.pmid: 16528384
references.citation: Nat Rev Neurol. 2011 Jul 05;7(8):439-50
references.pmid: 21727940
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):618-23
references.pmid: 17202265
references.citation: Mol Cell Oncol. 2014 Dec 23;1(3):e963478
references.pmid: 27308348
references.citation: Genes Dev. 2007 Nov 1;21(21):2683-710
references.pmid: 17974913
references.citation: Sci Rep. 2014 Jan 10;4:3631
references.pmid: 24406986
references.citation: Cancer Immunol Res. 2014 Sep;2(9):823-30
references.pmid: 25187272
references.citation: Cancer Cell. 2006 Mar;9(3):157-73
references.pmid: 16530701
references.citation: Science. 2012 Nov 23;338(6110):1080-4
references.pmid: 23087000
references.citation: Clin Cancer Res. 2004 Aug 15;10(16):5595-603
references.pmid: 15328202
references.citation: PLoS One. 2014 May 05;9(5):e95404
references.pmid: 24798348
references.citation: Arthritis Rheum. 2005 Mar;52(3):951-8
references.pmid: 15751079
references.citation: Mol Ther. 2003 Oct;8(4):666-73
references.pmid: 14529840
references.citation: PLoS One. 2013;8(2):e57489
references.pmid: 23451236
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18754-9
references.pmid: 18000063
references.citation: J Natl Cancer Inst. 2006 Dec 20;98 (24):1777-85
references.pmid: 17179479
references.citation: Cancer Cell. 2013 Sep 9;24(3):331-46
references.pmid: 23993863
references.citation: BMC Cancer. 2009 Oct 19;9:372
references.pmid: 19840379
references.citation: Nat Med. 2009 Jan;15(1):110-6
references.pmid: 19122659
references.citation: Nature. 2002 Jun 20;417(6891):861-6
references.pmid: 12075355
references.citation: J Clin Invest. 2007 Apr;117(4):889-901
references.pmid: 17380205
references.citation: IEEE Trans Biomed Eng. 2010 Oct;57(10):2617-21
references.pmid: 20656651
references.citation: Science. 2000 Sep 1;289(5484):1550-4
references.pmid: 10968790
references.citation: Biomaterials. 2002 Jul;23(13):2773-81
references.pmid: 12059028
references.citation: Nat Rev Cancer. 2010 May;10(5):319-31
references.pmid: 20414201
references.citation: Mol Cancer. 2007 Jan 16;6:6
references.pmid: 17227585
references.citation: J Immunol. 2007 Sep 1;179(5):2681-5
references.pmid: 17709478
references.citation: Nature. 2006 Dec 7;444(7120):756-60
references.pmid: 17051156
references.citation: Neuron. 2008 Jun 26;58(6):832-46
references.pmid: 18579075
references.citation: Glia. 2011 Aug;59(8):1190-9
references.pmid: 21446051
references.citation: Nat Cell Biol. 2012 Feb 12;14(3):257-65
references.pmid: 22327365
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17450-5
references.pmid: 21969599
references.citation: Nature. 2010 Jan 21;463(7279):318-25
references.pmid: 20032975
references.citation: Cancer Cell. 2010 Jan 19;17(1):98-110
references.pmid: 20129251
references.citation: Oncogene. 2016 Feb 4;35(5):608-20
references.pmid: 25961929
references.citation: Genes Dev. 2004 Sep 15;18(18):2195-224
references.pmid: 15371334