Downregulation of BMI-1 enhances 5-fluorouracil-induced apoptosis in nasopharyngeal carcinoma cells.
5-Fluorouracil (5-FU) is an important chemotherapeutic agent for nasopharyngeal carcinoma (NPC). However, drug resistance may occur after several cycles of 5-FU-based chemotherapy. The oncogene B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI-1) has been shown to be involved in the protection of cancer cells from apoptosis. In this study, 5-FU treatment could increase the percentage of apoptotic NPC cells among BMI-1/RNAi-transfected cells than that among cells transfected with the empty vector. The 50% inhibitory concentration (IC(50)) values of 5-FU were significantly decreased to a greater extent in the cells transfected with BMI-1/RNAi. Most importantly, the expression of phospho-AKT and the anti-apoptotic protein BCL-2 were downregulated in the cells in which BMI-1 expression was inhibited, whereas the apoptosis-inducer BAX was observed to be upregulated. Abrogation of AKT pathway by a PI3K inhibitor could not further increase the sensitivity to 5-FU in the cells with reduced BMI-1 expression. Taken together, BMI-1 depletion enhanced the chemosensitivity of NPC cells by inducing apoptosis; which is associated with inhibition of the PI3K/AKT pathway.
Qin
Li
L
Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha 410078, China.
Zhang
Xing
X
Zhang
Ling
L
Feng
Yan
Y
Weng
Gui-Xiang
GX
Li
Man-Zhi
MZ
Kong
Qing-Li
QL
Qian
Chao-Nan
CN
Zeng
Yi-Xin
YX
Zeng
Mu-Sheng
MS
Liao
Duan-Fang
DF
Song
Li-Bing
LB
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics*; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors
D000964:Antimetabolites, Antineoplastic; C069077:BMI1 protein, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D051028:bcl-2-Associated X Protein; D063150:Polycomb Repressive Complex 1; D051057:Proto-Oncogene Proteins c-akt; D005472:Fluorouracil