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-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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 699-709 |
| Number of pages | 11 |
| Journal | American Journal of Pathology |
| Volume | 176 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2010 |
Funding
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.).
ASJC Scopus subject areas
- Pathology and Forensic Medicine
