NF-kappaB and STAT3 signaling in glioma: targets for future therapies

Abstract

Glioblastoma remains the most clinically challenging tumor of the CNS, as evidenced by the dismal change in overall survival over the past 50 years. However, recent advances in high-throughput screening techniques have given rise to a wealth of new information regarding the aberrant signaling pathways that drive the tumor phenotype. Two of these so-called 'oncopathways' are NF-kappaB and JAK/STAT. This review will describe the basic mechanisms of these pathways, explore the relevance of NF-kappaB and JAK/STAT signaling in glioblastoma, and look ahead to experimental compounds that will integrate our knowledge of these pathways into existing therapies.

Figure 1. The NF-κB signaling pathway

(A) The structure of NFkB proteins. NF-κB proteins are defined by a C-terminal RHD, which can be activated by phosphorylation. p65, RelB and c-Rel contain TAD, which can activate NF-κB target genes. p100 and p105 lack TADs but contain AR domains and N-terminal DDs. RelB also contains a LZ. (B) TNF-α is one of the most potent activators of NF-κB,and is produced in the CNS by microglia, astrocytes, endothelial cells and some neurons. TNF-α binds to the TNF-α receptor and activates the IKK kinase, which consists of three subunits: α, β and γ. IKK phosphorylates (yellow circles) the inhibitory protein IκBα and targets this protein for Ub mediated degradation. The liberated NF-κB dimer translocates into the nucleus, undergoes phosphorylation (yellow circle) and/or acetylation (green circle), and binds to κB elements in the promoters of target genes to regulate gene expression. AR: Ankyrin repeat; DD: Death domain; IKK: IκB kinase; LZ: Leucine zipper domain; RHD: Rel homology domain; TAD: Transactivation domains; Ub: Ubiquitin.

Figure 2. IL-6 family signaling through the JAK/STAT-3 pathway

OSM binding to the OSM receptor activates intracellular JAK kinases, predominantly JAK2, which phosphorylate (yellow circles) STAT-3. Once phosphorylated, STAT-3 molecules dimerize, translocate to the nucleus and bind to STAT response elements in the promoters of target genes. OSM: Oncostatin-M.