Bmi-1 induces radioresistance in MCF-7 mammary carcinoma cells.
Bmi-1, a member of the polycomb family, it is involved in self renewal of             stem cells and functions as an oncogene in many malignant human cancer types.             Recent studies have demonstrated that Bmi-1 is a predictive factor for poor patient             prognosis. However, the underlying mechanisms of radioresistance mediated by Bmi-1             are poorly understood. In this study, the dose-survival relationship was analyzed             using a clonogenic survival assay and combined radiation treatment with Bmi-1             overexpression or silencing. DNA double-strand break (DSB) and repair was assessed             by immunofluorescence staining of γH2AX foci. In addition, mitochondrial membrane             potential was detected between Bmi-1 knockdown and control MCF-7 cells after irradiation.             Apoptosis and cell cycle were evaluated by flow cytometry. We found that exposure             of MCF-7 cells overexpressing Bmi-1 to ionizing radiation resulted in dramatically             enhanced survival relative to control cells, whereas cells with silenced Bmi-1             showed markedly reduced survival. Bmi-1 inhibition significantly increased DSBs             and decreased DSB repair. Furthermore, Bmi-1 knockdown induced loss of mitochondrial             membrane potential and enhanced apoptosis by up-regulating p53, p21, Bax expression             and down-regulating p-AKT and Bcl-2 expression. These results indicate that Bmi-1             may play an important role in radiosensitivity, and the suppression of its expression             might be a potential therapeutic target for breast cancer.
State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China.
Zhi-Gang
ZG
Liu
Li
L
Liu
Li-Hua
LH
Xu
Wei
W
Yi
Ya-Lan
YL
Tao
Zi-Wei
ZW
Tu
Man-Zhi
MZ
Li
Mu-Sheng
MS
Zeng
Yun-Fei
YF
Xia
D017209:Apoptosis / Q000528:radiation effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000528:radiation effects; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D011836:Radiation Tolerance / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494826:BAX protein, human; C069077:BMI1 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C468783:H2AX protein, human; D006657:Histones; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D063150:Polycomb Repressive Complex 1; D051057:Proto-Oncogene Proteins c-akt