Gomez Lourdes A, de Las Pozas Alicia, Reiner Teresita, Burnstein Kerry, Perez-Stable Carlos
Geriatric Research, Education, and Clinical Center and Research Service, VA Medical Center, University of Miami Miller School of Medicine, 1201 Northwest 16 Street, Miami, FL 33125, USA.
Mol Cancer Ther. 2007 May;6(5):1534-43. doi: 10.1158/1535-7163.MCT-06-0727.
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.
理想的化疗药物应利用转化细胞与正常细胞之间的差异，仅诱导癌细胞凋亡。其中一个差异可能是癌细胞中细胞周期蛋白B1（Cyclin B1）蛋白的过表达，这是有丝分裂正常进行所必需的。此前，我们发现用2-甲氧基雌二醇（2-ME）或多西他赛处理人前列腺癌细胞会导致Cyclin B1蛋白积累和Cyclin B1激酶活性增加，随后诱导凋亡性细胞死亡。抑制Cyclin B1激酶可降低2-ME和多西他赛诱导的凋亡。在本研究中，我们在前列腺癌细胞中建立了Cyclin B1蛋白与化疗诱导的凋亡之间的正相关关系。在未转化细胞中，Cyclin B1极少，化疗也不会诱导凋亡。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Cyclin B1小干扰RNA以降低Cyclin B1蛋白或表达显性负性细胞周期蛋白依赖性激酶1以抑制Cyclin B1激酶的LNCaP细胞凋亡减少。Cyclin B1过表达导致对凋亡的敏感性增加可能是由于Bcl-2水平降低、p53水平升高以及神经内分泌分化减少。我们认为一种癌症特异性机制，即2-ME和多西他赛可能发挥抗前列腺癌活性的机制是Cyclin B1激酶的失调激活，导致凋亡性细胞死亡的诱导。我们的结果还表明，前列腺癌细胞中较高水平的Cyclin B1可能是化疗的良好预后标志物。
