Morphoproteomic demonstration of constitutive nuclear factor-kappaB activation in glioblastoma multiforme with genomic correlates and therapeutic implications.

Glioblastoma multiforme (GBM) presents a major challenge to neurosurgeons, neuro-oncologists, and radiation therapists by virtue of its location with a blood-brain barrier, chemoradioresistance, highly malignant phenotype, and angiogenic potential. Because nuclear factor-kappaB (NF-kappaB) can transcriptionally activate genes leading to the synthesis of anti-apoptotic, chemoresistant, growth promoting, and angiogenic proteins; we assessed the state of activation of NF-kappaB in 6 GBM cases at diagnosis. Morphoproteomic analysis confirmed the constitutive activation of NF-kappaB by demonstrating the phosphorylation (p) and nuclear translocation of p-NF-kappaBp65 (Ser 536) in these cases. This observation coincides with (a) previous immunohistochemical findings showing nuclear translocation of total p65, (b) demonstration of NF-kappaB DNA binding activity, (c) the results of electrophoretic mobility shift assays, and (d) existing genomic data in GBM. Furthermore, such constitutive activation of the NF-kappaB pathway helps to explain some of the tumor biology and supports the incorporation of NF-kappaB pathway inhibitors into the treatment of GBM.