title: Inhibition of NF-κB signaling commits resveratrol-treated medulloblastoma cells to apoptosis without neuronal differentiation.
abstract: 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.
authors.affiliation: Department of Cell Biology and Liaoning Laboratory of Cancer Genomics, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Wen
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Mo-Li
authors.initials: ML
authors.lastname: Wu
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Fan
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Shu
authors.forename: Qing-You
authors.initials: QY
authors.lastname: Kong
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Chen
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008527:Medulloblastoma / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D040081:Protein Array Analysis; D000077185:Resveratrol; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors
chemical_list: D016588:Anticarcinogenic Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D013267:Stilbenes; D013778:Tetrazolium Salts; D013844:Thiazoles; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D011392:Proline; C022616:thiazolyl blue; D000077185:Resveratrol