Qin Li, Zhang Xing, Zhang Ling, Feng Yan, Weng Gui-Xiang, Li Man-Zhi, Kong Qing-Li, Qian Chao-Nan, Zeng Yi-Xin, Zeng Mu-Sheng, Liao Duan-Fang, Song Li-Bing
Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha 410078, China.
Biochem Biophys Res Commun. 2008 Jul 4;371(3):531-5. doi: 10.1016/j.bbrc.2008.04.117. Epub 2008 Apr 29.
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.
5-氟尿嘧啶（5-FU）是鼻咽癌（NPC）重要的化疗药物。然而，基于5-FU的化疗几个周期后可能会出现耐药。致癌基因B细胞特异性莫洛尼鼠白血病病毒插入位点1（BMI-1）已被证明参与保护癌细胞免于凋亡。在本研究中，与转染空载体的细胞相比，5-FU处理可使BMI-1/RNAi转染细胞中凋亡的NPC细胞百分比增加。在转染BMI-1/RNAi的细胞中，5-FU的50%抑制浓度（IC50）值显著降低得更多。最重要的是，在BMI-1表达被抑制的细胞中，磷酸化AKT和抗凋亡蛋白BCL-2的表达下调，而凋亡诱导剂BAX则上调。用PI3K抑制剂阻断AKT途径并不能进一步增加BMI-1表达降低的细胞对5-FU的敏感性。综上所述，BMI-1缺失通过诱导凋亡增强了NPC细胞的化疗敏感性；这与PI3K/AKT途径的抑制有关。
