Oncoprotein Bmi-1 Renders Apoptotic Resistance to Glioma Cells through Activation of the IKK-Nuclear Factor-κB Pathway
Oncoprotein Bmi-1 Renders Apoptotic Resistance to Glioma Cells through Activation of the IKK-Nuclear Factor-κB Pathway
复制标题
癌蛋白 Bmi-1 通过激活 IKK-核因子-kappaB 通路，对神经胶质瘤细胞产生凋亡抵抗。
DOI：
10.2353/ajpath.2010.090502
复制
发表时间：
2010-02-01
影响因子：
6
通讯作者：
Li, Mengfeng
中科院分区：
文献类型：
--
作者：
Li, Jun;Gong, Li-Yun;Li, Mengfeng
恶性胶质瘤的特征之一是其对细胞毒性试剂诱导的细胞凋亡的异常抵抗。Bmi-1是一种癌蛋白，与包括神经胶质瘤在内的各种人类癌症的发生和癌症进展有关。然而，Bmi-1抗凋亡功能的潜在机制在很大程度上仍然未知。在这项研究中，我们报告Bmi-1通过核因子-κ B（NF-κ B）对胶质瘤细胞产生凋亡抵抗。在神经胶质瘤细胞中，Bmi-1的异位表达通过减少活化的半胱天冬酶-3和PARP以及诱导Bcl-X（L）而显著抑制阿霉素、BCNU或UV辐射诱导的细胞凋亡。Bmi-1的细胞缺失增强了胶质瘤细胞对阿霉素、BCNU或UV照射诱导的凋亡的敏感性。Bmi-1通过刺激IkappaB磷酸化、核转位和NF-κ B的转录活性以及NF-κ B的下游基因（包括胱天蛋白酶-3、PARP、Bcl-X（L）和c-Myc）的表达来激活NF-κ B。IKK-NF-kappaB通路的抑制消除了Bmi-1对胶质瘤细胞的抗凋亡作用在高级别胶质瘤中，Bmi-1和NF-κ B在细胞核中共表达。Bmi-1的上调也与胶质瘤患者的肿瘤进展和不良生存相关。总之，我们的数据表明Bmi-1通过IKK-NF-kappaB通路赋予胶质瘤细胞凋亡抗性，并建议Bmi-1作为胶质瘤预后的有用指标。
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-kappaB (NF-kappaB). 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-kappaB through stimulation of IkappaB phosphorylation, nuclear translocation, and transcriptional activity of NF-kappaB and expression of downstream genes of NF-kappaB including caspase-3, PARP, Bcl-X(L), and c-Myc. Inhibition of the IKK-NF-kappaB pathway abrogates the antiapoptotic effect of Bmi-1 on glioma cells. In high-grade gliomas, Bmi-1 and NF-kappaB 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-kappaB pathway and suggest Bmi-1 as a useful indicator for glioma prognosis.