Androic Ilija, Krämer Andrea, Yan Ruilan, Rödel Franz, Gätje Regine, Kaufmann Manfred, Strebhardt Klaus, Yuan Juping
Department of Obstetrics and Gynecology, School of Medicine, J,W, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
BMC Cancer. 2008 Dec 29;8:391. doi: 10.1186/1471-2407-8-391.
Cyclin B1, the regulatory subunit of cyclin-dependent kinase 1 (Cdk1), is essential for the transition from G2 phase to mitosis. Cyclin B1 is very often found to be overexpressed in primary breast and cervical cancer cells as well as in cancer cell lines. Its expression is correlated with the malignancy of gynecological cancers.
In order to explore cyclin B1 as a potential target for gynecological cancer therapy, we studied the effect of small interfering RNA (siRNA) on different gynecological cancer cell lines by monitoring their proliferation rate, cell cycle profile, protein expression and activity, apoptosis induction and colony formation. Tumor formation in vivo was examined using mouse xenograft models.
Downregulation of cyclin B1 inhibited proliferation of several breast and cervical cancer cell lines including MCF-7, BT-474, SK-BR-3, MDA-MB-231 and HeLa. After combining cyclin B1 siRNA with taxol, we observed an increased apoptotic rate accompanied by an enhanced antiproliferative effect in breast cancer cells. Furthermore, control HeLa cells were progressively growing, whereas the tumor growth of HeLa cells pre-treated with cyclin B1 siRNA was strongly inhibited in nude mice, indicating that cyclin B1 is indispensable for tumor growth in vivo.
Our data support the notion of cyclin B1 being essential for survival and proliferation of gynecological cancer cells. Concordantly, knockdown of cyclin B1 inhibits proliferation in vitro as well as in vivo. Moreover, targeting cyclin B1 sensitizes breast cancer cells to taxol, suggesting that specific cyclin B1 targeting is an attractive strategy for the combination with conventionally used agents in gynecological cancer therapy.
细胞周期蛋白B1是细胞周期蛋白依赖性激酶1（Cdk1）的调节亚基，对从G2期向有丝分裂的转变至关重要。细胞周期蛋白B1在原发性乳腺癌和子宫颈癌细胞以及癌细胞系中经常被发现过表达。其表达与妇科癌症的恶性程度相关。
为了探索细胞周期蛋白B1作为妇科癌症治疗的潜在靶点，我们通过监测不同妇科癌细胞系的增殖率、细胞周期分布、蛋白质表达和活性、凋亡诱导及集落形成，研究了小干扰RNA（siRNA）对它们的影响。使用小鼠异种移植模型检测体内肿瘤形成情况。
细胞周期蛋白B1的下调抑制了包括MCF-7、BT-474、SK-BR-3、MDA-MB-231和HeLa在内的几种乳腺癌和子宫颈癌细胞系的增殖。将细胞周期蛋白B1 siRNA与紫杉醇联合使用后，我们观察到乳腺癌细胞的凋亡率增加，同时抗增殖作用增强。此外，对照HeLa细胞逐渐生长，而用细胞周期蛋白B1 siRNA预处理的HeLa细胞在裸鼠中的肿瘤生长受到强烈抑制，这表明细胞周期蛋白B1对体内肿瘤生长不可或缺。
我们的数据支持细胞周期蛋白B1对妇科癌细胞的存活和增殖至关重要这一观点。相应地，细胞周期蛋白B1的敲低在体外和体内均抑制增殖。此外，靶向细胞周期蛋白B1使乳腺癌细胞对紫杉醇敏感，这表明特异性靶向细胞周期蛋白B1是与妇科癌症治疗中常规使用的药物联合使用的有吸引力的策略。
