Oncoprotein Bmi-1 Renders Apoptotic Resistance to Glioma Cells through Activation of the IKK-Nuclear Factor-kappa B Pathway

作者：Li Jun; Gong Li Yun; Song Li Bing; Jiang Li Li; Liu Li Ping; Wu Jueheng; Yuan Jie; Cai Jun Chao; He Mian; Wang Lan; Zeng Musheng; Cheng Shi Yuan; Li Mengfeng^*

来源：AMERICAN JOURNAL OF PATHOLOGY, 2010, 176(2): 699-709.

DOI：10.2353/ajpath.2010.090502

One of the features of malignant gliomas is their deviant resistance to cellular apoptosis induced by cytotoxic reagents. Bmi-1, an oncoprotein, has been linked to oncogenesis; and cancer progression in various types of human cancers including gliomas. However, the mechanisms underlying Bmi-1 antiapoptotic function remain largely unknown. in this study, we report that Bmi-1 renders apoptotic resistance to glioma. cells through nuclear factor-icil (NF-kappa B). In glioma cells, ectopic expression of Bmi-1 significantly inhibits doxorubicin-, BCNU-, or UV irradiation-induced apoptosis through reduction of activated caspase-3 and PARP, and induction of Bcl-X(L). Cellular depletion of Bmi-1 enhances the sensitivity of glioma cells to apoptosis induced by doxorubicin, BCNU, or UV irradiation. Bmi-1 activates NF-kappa B through stimulation of I kappa B phosphorylation, nuclear translocation, and transcriptional activity of NF-kappa B and expression of downstream genes of NF-kappa B including caspase-3, PARP, Bcl-X(L), and c-Myc. Inhibition of the IKK-NF-kappa B pathway abrogates the antiapoptotic effect of Bmi-1 on glioma cells. In high-grade gliomas, Bmi-1 and NF-kappa B are co-expressed in the cell nucleus. Up-regulation of Bmi-1 also correlates with tumor progression and poor survival of patients with gliomas. Together, our data demonstrate that Bmi-1 bestows apoptotic resistance to glioma cells through the IKK-NF-kappa B pathway and suggest Bmi-1 as a useful indicator for glioma prognosis. (Am J Pathol 2010, 176:699-709; DOT: 10.2353/ajpath.2010.090502)

• 单位
  2; 中山大学