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Inhibition of Nuclear Factor-B Activation Confers Sensitivity to Tumor Necrosis Factor- by Impairment of Cell Cycle Progression in Human Glioma Cells¹

Department of Endocrinology and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601 [G.O., T.N., H.S.]; and Department of Neurosurgery, Nagoya University School of Medicine, Nagoya 466-8550 [G.O., K.S., M.M., J.Y.], Japan

Tumor necrosis factor (TNF)- has been shown to exert cytotoxic or cytostatic effects on tumor cells, but susceptibility to TNF- varies among different types of cells. TNF- activates a transcription factor, nuclear factor-B (NF-B), which induces a wide variety of genes and causes pleiotrophic responses. In this study, the relationship between susceptibility to TNF- and activation of NF-B was investigated in six human malignant glioma cell lines. Cell proliferation analysis revealed that only one cell line, SK-MG-1, was sensitive to TNF- and that the other five, including U-251MG, were resistant. Electrophoretic mobility-shift assay showed that TNF- strongly activated a subtype of NF-B, the p50-p65 heterodimer, in all of the resistant cell lines tested. However, this activation was weak in the sensitive cell line, SK-MG-1. Activation of NF-B by TNF- in the resistant cell lines resulted in a significant increase of a reporter gene expression driven by NF-B site, suggesting a possibility that activation of p50-p65 confers resistance to TNF-. To test this hypothesis, we established a stable cell line that expresses an inducible dominant negative NF-B (p65 DN) protein in one of the TNF--resistant cell lines, U-251MG. In the established clone, induction of p65 DN protein decreased TNF--dependent increase in the DNA binding of p50-p65 heterodimer and NF-B-dependent reporter gene activity. Although no growth inhibition of this clone was observed by TNF- treatment, induction of p65 DN together with TNF- resulted in a significant decrease in cell number. Cell cycle analysis revealed that this growth inhibition was due to the impairment of cell cycle progression. These results indicate that an active NF-B complex, such as the p50-p65 heterodimer, plays a crucial role in the progression of cell cycle in malignant glioma cells. Refractoriness to TNF- treatment could be prevented by inhibiting NF-B activation.

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