I-Kappa-B Kinase-epsilon activates nuclear factor-kappa B and STAT5B and supports glioblastoma growth but amlexanox shows little therapeutic potential in these tumors

Aim: This study aims to analyze the role of I-kappa-B kinase (IKK)-epsilon in glioblastoma (GBM). Methods: A series of in vitro , in vivo , microarray, and immunohistochemical assessments were performed to evaluate the biological effects of IKK-epsilon on cell signaling, radiation sensitivity, and patient survival in GBM condition. Results: IKK-epsilon was strongly expressed in 75% of 195 primary GBM samples but did not correlate with patient survival. No correlation was established between the copy number, messenger RNA (mRNA) expression, and protein expression in 38 fresh tumor samples, nor between IKK-epsilon mRNA expression and survival in 543 GBM of the TCGA repository. In vitro , IKK-epsilon contributed to the growth and migration of glioma cells, independent of their EGFR VIII status. IKK-epsilon activated nuclear factor (NF)-κB and STAT5B in vitro , confirming the observed correlation surgical GBM samples. IKK-epsilon silencing did not alter the sensitivity of GBM cells to ionizing radiation. Amlexanox, inhibitor of IKK-epsilon and TBK1, poorly (IC50 u003e 100 μM) decreased cell growth and increased NF-κB activity in GBM cells, in vitro , notably due to TBK1 inhibition. In vivo , oral amlexanox failed to inhibit the growth of intracerebral U87 GBM xenografts in nude mice. Conclusion: The results confirm a moderate pro-oncogenic role of IKK-epsilon in GBM, but question the potential of amlexanox as a therapeutic drug.