Increased expression of cyclin B1 sensitizes prostate cancer cells to apoptosis induced by chemotherapy
Increased expression of cyclin B1 sensitizes prostate cancer cells to apoptosis induced by chemotherapy
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DOI：
10.1158/1535-7163.mct-06-0727
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发表时间：
2007-05-01
影响因子：
5.7
通讯作者：
Perez-Stable, Carlos
中科院分区：
文献类型：
--
作者：
Gomez, Lourdes A.;de las Pozas, Alicia;Perez-Stable, Carlos
理想的化疗药物应该利用转化细胞和正常细胞之间的差异，只在癌细胞中诱导凋亡。一个这样的差异可能是癌细胞中细胞周期蛋白B1蛋白的过度表达，这是通过有丝分裂的适当进展所必需的。以前，我们表明，2-甲氧基紫杉醇（2-ME）或多西他赛的人前列腺癌细胞的治疗结果在细胞周期蛋白B1蛋白的积累和细胞周期蛋白B1激酶活性的增加，随后诱导细胞凋亡性死亡。抑制细胞周期蛋白B1激酶可降低2-ME和多西他赛诱导的细胞凋亡。在这项研究中，我们建立了细胞周期蛋白B1蛋白和化疗诱导的前列腺癌细胞凋亡之间的正相关性。有最小的细胞周期蛋白B1和诱导细胞凋亡的化疗非转化细胞。稳定过表达cyclin B1的LNCaP和PC-3前列腺癌细胞对化疗诱导的凋亡更敏感。表达细胞周期蛋白B1小干扰RNA以降低细胞周期蛋白B1蛋白或显性负性细胞周期蛋白依赖性激酶1以抑制细胞周期蛋白B1激酶的LNCaP细胞显示凋亡减少。细胞周期蛋白B1过表达增加对细胞凋亡的敏感性可能是由于Bcl-2降低、p53升高和神经内分泌分化降低。我们认为，2-ME和多西他赛可能发挥抗前列腺癌活性的癌症特异性机制是细胞周期蛋白B1激酶的激活失调，导致诱导凋亡性细胞死亡。我们的研究结果还表明，前列腺癌细胞中较高水平的细胞周期蛋白B1可能是化疗的一个良好的预后标志物。
Chemotherapeutic drugs ideally should take advantage of the differences between transformed and normal cells and induce apoptosis only in cancer cells. One such difference may be the overexpression of cyclin B1 protein in cancer cells, which is required for the proper progression through mitosis. Previously, we showed that treatment of human prostate cancer cells with 2-methoxyestradiol (2-ME) or docetaxel results in an accumulation of cyclin B1 protein and an increase in cyclin B1 kinase activity, followed by induction of apoptotic cell death. Inhibition of cyclin B1 kinase lowers apoptosis induced by 2-ME and docetaxel. In this study, we established a positive correlation between cyclin B1 protein and apoptosis induced by chemotherapy in prostate cancer cells. There is minimal cyclin B1 and induction of apoptosis by chemotherapy in nontransformed cells. LNCaP and PC-3 prostate cancer cells stably overexpressing cyclin B1 are more sensitive to apoptosis induced by chemotherapy. LNCaP cells expressing cyclin B1 small interfering RNA to lower cyclin B1 protein or dominant negative cyclin-dependent kinase 1 to inhibit cyclin B1 kinase show a decrease in apoptosis. Increased sensitivity to apoptosis by overexpression of cyclin B1 may be due to lower Bcl-2, higher p53, and decreased neuroendocrine differentiation. We suggest that a cancer-specific mechanism whereby 2-ME and docetaxel may exert anti-prostate cancer activity is the deregulated activation of cyclin B1 kinase, leading to the induction of apoptotic cell death. Our results also suggest that higher levels of cyclin B1 in prostate cancer cells may be a good prognostic marker for chemotherapy.