Resveratrol promotes differentiation and apoptosis of
medulloblastoma cells by suppressing STAT3 signaling and a range of
cancer-associated gene expression. However, Bcl-2, a common target of STAT3 and NF-κB signaling, is distinctly up-regulated in
resveratrol-treated
medulloblastoma cells, indicating potential effects of NF-κB in Bcl-2 expression and anti-
medulloblastoma efficiency of
resveratrol. To clarify this point, the status of NF-κB signaling and the consequence of NF-κB inhibition in UW228-2 and UW228-3
medulloblastoma cells without and with
resveratrol treatment were evaluated by several experimental approaches. The results revealed that
resveratrol activated NF-κB signaling in both cell lines at the 4-h treatment point, and the treated cells sequentially exhibited Bcl-2 up-regulation, neuronal-like phenotype with synaptophisin expression, and, eventually, apoptosis.
Pyrrolidine dithiocarbamate (
PDTC) treatment inhibited NF-κB activation and Bcl-2 expression and committed
resveratrol-treated cells to apoptosis at the 8-h time point without the step of neuron-oriented differentiation. On the other hand, a single 50 μg/ml
lipopolysaccharide (LPS) treatment activated NF-κB signaling accompanied with sustained proliferation and neuron-like differentiation. Tissue microarray-based immunohistochemical staining showed significantly different (P < 0.001) p65 nuclear translocation between the neurons of
tumor-surrounding cerebella (10/10; 100%) and
medulloblastoma tissues (20/117; 17.09%). Additionally,
synaptophysin production was found in 83.64% of p65-positive and in 40.35% of p65-negative
medulloblastoma cases. Our in-vitro and in-vivo results thus demonstrate the dual effects of NF-κB signaling on
medulloblastoma cells by delaying
resveratrol-induced apoptosis by up-regulating Bcl-2 expression or by involvement in neuronal-like differentiation in the absence of
resveratrol. Therefore, appropriate inhibition of NF-κB activation may enhance the anti-
medulloblastoma efficacy of
resveratrol.