Targeting NF-κB in glioblastoma: A therapeutic approach.
Dinorah Friedmann-MorvinskiRajesh NarasimamurthyYifeng XiaChad MyskiwYasushi SodaInder M VermaPublished in: Science advances (2016)
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.
Keyphrases
- nuclear factor
- signaling pathway
- lps induced
- pi k akt
- oxidative stress
- toll like receptor
- rna seq
- endothelial cells
- inflammatory response
- mouse model
- single cell
- gene expression
- cell proliferation
- long non coding rna
- binding protein
- diabetic rats
- optical coherence tomography
- high glucose
- induced pluripotent stem cells
- protein kinase
- single molecule