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Inhibition of NF-κB signaling commits resveratrol-treated medulloblastoma cells to apoptosis without neuronal differentiation

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
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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.

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Acknowledgments

We gratefully acknowledge J.R. Silber for providing UW228-2 and UW228-3 cells. We thank Professor Xiang-Hong Yang for providing human medulloblastoma specimens. This work is supported by the grants from National Natural Science Foundation of China (nos. 30527002, 30670946, 30971038, and 81072063) and by the special fund for Liaoning Provincial Laboratory (no. LS2010055).

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Authors and Affiliations

  1. Department of Cell Biology and Liaoning Laboratory of Cancer Genomics, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China

    Shu Wen, Hong Li, Mo-Li Wu, Shao-Hua Fan, Qian Wang, Xiao-Hong Shu, Qing-You Kong, Xiao-Yan Chen & Jia Liu

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  1. Shu Wen
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  2. Hong Li
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Correspondence to Jia Liu.

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Wen, S., Li, H., Wu, ML. et al. Inhibition of NF-κB signaling commits resveratrol-treated medulloblastoma cells to apoptosis without neuronal differentiation. J Neurooncol 104, 169–177 (2011). https://doi.org/10.1007/s11060-010-0496-y

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  • DOI: https://doi.org/10.1007/s11060-010-0496-y

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