Aberrant constitutive activation of nuclear factor kappaB in glioblastoma multiforme drives invasive phenotype.

ABSTRACT

Several recent studies have shown that aberrant constitutive activation of nuclear factor kappaB (NF-kappaB) is present in a variety of cancers including gliomas. NF-kappaB is known to play important roles in the physiological regulation of diverse cellular processes such as inflammation, growth and immunity. In contrast, aberrant activation of this latent transcription factor promotes cancer cell migration, invasion and resistance to chemotherapy. Here we show by electro-mobility shift assay (EMSA) and immuno-staining that constitutive NF-kappaB activation is present in various malignant glioma cell lines as well as in primary cultures derived from tumor tissue. This activation was not serum dependent and it led to high IL-8 gene transcription and protein production. Over-expression of an I-kappaB super-repressor (I-kappaB SR) transgene completely blocked constitutive NF-kappaB activation, nuclear localization and transcription of some but not all NF-kappaB regulated genes indicating that NF-kappaB signaling in glioma cells is I-kappaB dependent. Surprisingly, over-expression of IkappaBSR did not have any effect on the transcription levels of anti-apoptotic genes in these glioma cultures and cell lines. Down-regulation of NF-kappaB activation reduced invasion of glioma cells through matrigel. Collectively these data suggest that aberrant constitutive activation of NF-kappaB in glioblastoma cells promotes their invasive phenotype. Interruption of this aberrant NF-kappaB activity may help reduce the spread of this infiltrative tumor.