TY - JOUR
T1 - Oncoprotein Bmi-1 renders apoptotic resistance to glioma cells through activation of the IKK-nuclear factor-κB pathway
AU - Li, Jun
AU - Gong, Li Yun
AU - Song, Li Bing
AU - Jiang, Li Li
AU - Liu, Li Ping
AU - Wu, Jueheng
AU - Yuan, Jie
AU - Cai, Jun Chao
AU - He, Mian
AU - Wang, Lan
AU - Zeng, Musheng
AU - Cheng, Shi Yuan
AU - Li, Mengfeng
N1 - Funding Information:
Supported by The Ministry of Science and Technology of China, grant (973)2005CB724605; The Natural Science Foundation of China (No. 30670803, 30770836, 30771110, 30870963, 30872930, 30831160517); Program for New Century Excellent Talents in Universities (No.NCET-07-0877); The Science and Technology Department of Guangdong Province, China (No.07001503, 8251008901000006); Ministry of Education of China [No.(2008)890 and No.200805580047]; The Science and Technology Department of Zhuhai Municipality, Guangdong Province, China (No. PC20071076); Guangdong Provincial Natural Science Foundation (No. 2006Z3-E4081), and a key grant from the 985-II project (To J.L., M.L., and L.B.S.) and grants US NIH CA102011, CA130966 and American Cancer Society (ACS) RSG CSM-107111 (to S.-Y.C.).
PY - 2010/2
Y1 - 2010/2
N2 - 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-κB (NF-κB). In glioma cells, ectopic expression of Bmi-1 significantly inhibits doxorubicin-, BCNU-, or UV irradiationinduced 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-κB through stimulation of IκB phosphorylation, nuclear translocation, and transcriptional activity of NF-κB and expression of downstream genes of NF-κB including caspase-3, PARP, Bcl-XL, and c-Myc. Inhibition of the IKK-NF-κB pathway abrogates the antiapoptotic effect of Bmi-1 on glioma cells. In high-grade gliomas, Bmi-1 and NF-κB 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 IKKNF-κB pathway and suggest Bmi-1 as a useful indicator for glioma prognosis.
AB - 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-κB (NF-κB). In glioma cells, ectopic expression of Bmi-1 significantly inhibits doxorubicin-, BCNU-, or UV irradiationinduced 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-κB through stimulation of IκB phosphorylation, nuclear translocation, and transcriptional activity of NF-κB and expression of downstream genes of NF-κB including caspase-3, PARP, Bcl-XL, and c-Myc. Inhibition of the IKK-NF-κB pathway abrogates the antiapoptotic effect of Bmi-1 on glioma cells. In high-grade gliomas, Bmi-1 and NF-κB 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 IKKNF-κB pathway and suggest Bmi-1 as a useful indicator for glioma prognosis.
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U2 - 10.2353/ajpath.2010.090502
DO - 10.2353/ajpath.2010.090502
M3 - Article
C2 - 20035051
AN - SCOPUS:76149111625
SN - 0002-9440
VL - 176
SP - 699
EP - 709
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 2
ER -