TY - JOUR
T1 - Targeting NF-kB in glioblastoma
T2 - A therapeutic approach
AU - Friedmann-Morvinski, Dinorah
AU - Narasimamurthy, Rajesh
AU - Xia, Yifeng
AU - Myskiw, Chad
AU - Soda, Yasushi
AU - Verma, Inder M.
PY - 2016/1
Y1 - 2016/1
N2 - 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 kB (NF-kB) activation showing enrichment of known NF-kB target genes. Inhibition of NF-kB by either depletion of IkB kinase 2 (IKK2), expression of a IkBaM super repressor, or using a NEMO (NF-kB essential modifier)-binding domain (NBD) peptide in tumor-derived cell lines attenuated tumor proliferation and prolonged mouse survival. Timp1, one of the NF-kB target genes significantly up-regulated in GBM, was identified to play a role in tumor proliferation and growth. Inhibition of NF-kB activity or silencing of Timp1 resulted in slower tumor growth in both mouse and human GBM models. Our results suggest that inhibition of NF-kB activity or targeting of inducible NF-kB genes is an attractive therapeutic approach for GBM.
AB - 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 kB (NF-kB) activation showing enrichment of known NF-kB target genes. Inhibition of NF-kB by either depletion of IkB kinase 2 (IKK2), expression of a IkBaM super repressor, or using a NEMO (NF-kB essential modifier)-binding domain (NBD) peptide in tumor-derived cell lines attenuated tumor proliferation and prolonged mouse survival. Timp1, one of the NF-kB target genes significantly up-regulated in GBM, was identified to play a role in tumor proliferation and growth. Inhibition of NF-kB activity or silencing of Timp1 resulted in slower tumor growth in both mouse and human GBM models. Our results suggest that inhibition of NF-kB activity or targeting of inducible NF-kB genes is an attractive therapeutic approach for GBM.
UR - http://www.scopus.com/inward/record.url?scp=84987654802&partnerID=8YFLogxK
U2 - 10.1126/sciadv.1501292
DO - 10.1126/sciadv.1501292
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C2 - 26824076
AN - SCOPUS:84987654802
SN - 2375-2548
VL - 2
JO - Science advances
JF - Science advances
IS - 1
M1 - e1501292
ER -