Journal
ONCOGENE
Volume 26, Issue 4, Pages 571-582Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1209841
Keywords
NF-kappa B; TRAIL; cytotoxic drugs; apoptosis; proteasome inhibition
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The transcription factor nuclear factor-kappaB (NF-kappa B) is a key regulator of stress-induced transcriptional activation and has been implicated in mediating primary or acquired apoptosis resistance in various cancers. In the present study, we therefore investigated the role of NF-kappa B in regulating apoptosis in malignant glioma, a prototypic tumor refractory to current treatment approaches. Here, we report that constitutive NF-KB DNA-binding activity was tow or moderate in eight different glioblastoma cell fines compared to Hodgkin's lymphoma cells, known to harbor aberrant constitutive NF-kappa B activity. Specific inhibition of NF-kappa B by overexpression of inhibitor of kappa B (I kappa B)a superrepressor did not enhance spontaneous apoptosis of glioblastoma cells. Also, overexpression of I kappa B alpha superrepressor had no significant impact on apoptosis induced by two prototypic classes of apoptotic stimuli, that is, chemotherapeutic drugs or death-inducing ligands such as TNF-related apoptosis inducing ligand (TRAIL), which are known to trigger NF-kappa B activation as part of a cellular stress response. Similarly, inhibition of NF-kappa B by the proteasome inhibitor MG132 did not increase doxorubicin (Doxo)-induced apoptosis of glioblastoma cells, although it prevented DNA binding of NF-kappa B complexes in response to Doxo. Interestingly, proteasome inhibition significantly sensitized glioblastoma cells for TRAIL-induced apoptosis. These findings indicate that the characteristic antiapoptotic function of NF-KB reported for many cancers is not a primary feature of glioblastoma and thus, specific NF-KB inhibition may not be effective for chemosensitization of glioblastoma. Instead, proteasome inhibitors, which enhanced TRAIL-induced apoptosis in an NF-kappa B-independent manner, may open new perspectives to increase the efficacy of TRAIL-based regimens
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