Glioblastoma multiforme (GBM) is one of the deadliest human cancers, with an average survival of around one year from the time of diagnosis. This poor prognosis is due to therapeutic resistance and tumor recurrence following surgical removal.
GBM is remarkably heterogeneous and may represent several unique entities with distinct cell types of origin and various genetic lesions, resulting in different clinical behaviors.
Although several reports have attempted to define the different molecular subtypes of GBM, two subtypes, termed proneural and mesenchymal (MES), appear robust and generally consistent among the different classifications proposed. Tumors classified into the MES subtype exhibit worse prognosis and have been correlated with poor radiation responses, high expression of CD44, and nuclear factor kB (NF-kB) activation.
NF-kB is a master regulator of cell survival, inflammation, and immunity, and is involved in a myriad of activities related to cellular functions. NF-kB activation pathways can be triggered by a variety of stimuli, including cytokines (tumor necrosis factor–a and interleukin-1b), pathogen-associated molecular patterns, ultraviolet and ionizing radiation, reactive oxygen species, growth factors, DNA damage, and oncogenic stress.
In a canonical pathway, NF-kB homodimers or heterodimers are retained in the cytoplasm through a noncovalent interaction with an inhibitory protein, IkB. In response to an external signal, the IkB protein is phosphorylated by the IkB kinase (IKK) complex, ubiquitinated, and degraded, leading NF-kB proteins to the nucleus.
The IKK complex contains IKK1/IKKa, IKK2/IKKb, and the NF-kB essential modifier (NEMO)/IKKg. Upon activation, the IKK complex phosphorylates the IkB inhibitor, marking it for degradation by the proteasomal degradation machinery. Once translocated to the nucleus, NF-kB dimers can bind to DNA and regulate the transcription of various genes involved in several aspects of cellular activities.
Authors 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.
These results suggest that inhibition of NF-kB activity or targeting of inducible NF-kB genes is an attractive therapeutic approach for GBM.
http://advances.sciencemag.org/content/2/1/e1501292
Edited
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