TBK1 inhibitor exerts anti-proliferative effect on glioblastoma multiforme cells.

2021 
Glioma are common malignant brain tumors, among which glioblastoma multiforme (GBM) has the worst prognosis. Different studies of GBM revealed that targeting nuclear-factor-κB (NF-κB) induced an attenuation tumor proliferation and prolonged cell survival. TBK1 (TANK {TRAF (TNF (tumor-necrosis-factor) receptor-associated factor)-associated NF-κB activator}-binding kinase 1) is a serine/threonine-protein kinase and it is a member of the IκB kinase (IKK) family, involved in NF-κB pathway activation. The aim of this study was to investigate the potential effect of BX795, an inhibitor of TBK1, in an in vitro and ex vivo model of GBM. GBM cell lines (U87 and U138) and primary GBM cells were treated with different concentrations of BX795 at different time-points (24, 48 and 72h) to evaluate cell viability, autophagy, inflammation and apoptosis. Our results demonstrated that BX795 10 μM was able to reduce cell viability, showing antiproliferative effect both in U87, U138 and primary GBM cells. Moreover, treatment with BX795 10 μM increased the pro-apoptotic proteins Bax, p53, caspase-3 and caspase-9 whereas the anti-apoptotic Bcl-2 expression was reduced. Additionally our results showed a marked decrease of autophagy following BX795 treatment, reducing Atg7, Atg 5/12 and AKT expression. The anti-inflammatory effect of BX795 was demonstrated by a significantly reduction of NIK, IKKα and TNF-α expression, accompanied by a down-regulation of angiogenesis. Furthermore, in primary GBMs cell, BX795 10 μM was able to reduce TBK1 pathway activation and SOX3 expression. In conclusion, these findings showed that TBK1 is involved in GBM proliferation demonstrating that the inhibitor BX795, thanks its abilities, could improve therapeutic strategies for GBM treatment.
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