Down-Regulation of BMI-1 Cooperates With Artemisinin on Growth Inhibition of Nasopharyngeal Carcinoma Cells
Down-Regulation of BMI-1 Cooperates With Artemisinin on Growth Inhibition of Nasopharyngeal Carcinoma Cells
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下调BMI-1协同青蒿素抑制鼻咽癌细胞生长
DOI：
10.1002/jcb.23114
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发表时间：
2011-07-01
影响因子：
4
通讯作者：
Zhu, Zhenyu
中科院分区：
文献类型：
--
作者：
Wu, Jing;Hu, Dong;Zhu, Zhenyu
青蒿素及其衍生物是公知的抗疟药物，特别可用于治疗对传统抗疟药物具有抗性的恶性疟原虫疟疾寄生虫的感染。青蒿素具有抑制癌细胞生长和抗血管生成活性的作用，包括许多耐药和耐辐射的癌细胞系。莫洛尼鼠白血病病毒插入位点1（BMI-1）已显示通过抑制p16（ink 4a）转录来调节增殖。众所周知，BMI-1在鼻咽癌细胞系中过度表达，并与肿瘤进展的晚期浸润阶段和不良预后相关。本研究分析了青蒿素对鼻咽癌细胞株（CNE-1和CNE-2，高分化细胞和低分化细胞）增殖的抑制作用。我们证明青蒿素诱导CNE-1和CNE-2细胞G1期阻滞。青蒿素抑制BMI-1在蛋白质和转录水平。BMI-1基因敲低使细胞对青蒿素更敏感，G1期增加，但BMI-1的过表达部分逆转了青蒿素诱导的G1期细胞阻滞。BMI-1的缺失可增强青蒿素诱导的p16蛋白表达的增加和CDK 4蛋白表达的减少。此外，BMI-1的过表达能够减弱青蒿素处理的细胞中p16的增加和CDK 4的减少。综上所述，BMI 1-p16/CDK 4轴参与了青蒿素诱导的鼻咽癌细胞G1期阻滞，提示青蒿素联合下调BMI-1可能增强对鼻咽癌细胞的生长抑制作用。J.细胞。112：1938-1948，2011. (C)2011 Wiley-Liss，Inc.
Artemisinin and its derivatives are well known antimalaria drugs, particularly useful for the treatment of infection of Plasmodium falciparum malaria parasites resistant to traditional antimalarial pharmaceuticals. Artemisinin has inhibitory effects on cancer cell growth and anti-angiogenetic activity, including many drug-and radiation-resistant cancer cell lines. Moloney murine leukemia virus insertion site 1 (BMI-1) has been shown to regulate proliferation by inhibiting p16(ink4a) transcription. It is well known that BMI-1 over-expression was found in nasopharyngeal carcinoma cell lines and correlated with advanced invasive stage of the tumor progression and poor prognosis. In the present investigation, we analyzed the inhibitory effects of artemisinin on proliferation of nasopharyngeal carcinoma cell lines (CNE-1 and CNE-2, well-differentiated cells, and poorly differentiated cells). We demonstrated that artemisinin induced G1 cell cycle arrest in CNE-1 and CNE-2 cells. Artemisinin inhibited BMI-1 both in protein and transcript levels. BMI-1 knockdown made the cells more sensitive to artemisinin with an increase in G1 phase, but over-expression of BMI-1 partially reversed the artemisinin-induced G1 cell cycle arrest. Depletion of BMI-1 was able to intensifying the increment of p16 and the reduction of CDK4 induced by artemisinin. In addition, over-expression of BMI-1 was capable of attenuating the increasing p16 and decreasing CDK4 in cells treated with artemisinin. Taking together, the BMI1-p16/CDK4 axis was involved in the artemisinin-driven G1 arrest in nasopharyngeal carcinoma cells, and these results indicated that a potential treatment that the combination of artemisinin and BMI-1 downregulation could enhance the growth inhibitory affects on nasopharyngeal carcinoma cells. J. Cell. Biochem. 112: 1938-1948, 2011. (C) 2011 Wiley-Liss, Inc.