title: Oncoprotein Bmi-1 renders apoptotic resistance to glioma cells through activation of the IKK-nuclear factor-kappaB Pathway.
abstract: 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.
authors.affiliation: Departments of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, Guangdong 510080, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Li-Yun
authors.initials: LY
authors.lastname: Gong
authors.forename: Li-Bing
authors.initials: LB
authors.lastname: Song
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Jiang
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Liu
authors.forename: Jueheng
authors.initials: J
authors.lastname: Wu
authors.forename: Jie
authors.initials: J
authors.lastname: Yuan
authors.forename: Jun-Chao
authors.initials: JC
authors.lastname: Cai
authors.forename: Mian
authors.initials: M
authors.lastname: He
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.forename: Musheng
authors.initials: M
authors.lastname: Zeng
authors.forename: Shi-Yuan
authors.initials: SY
authors.lastname: Cheng
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D063150:Polycomb Repressive Complex 1; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: C069077:BMI1 protein, human; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D051550:I-kappa B Kinase