Cyclin A-associated kinase activity is needed for paclitaxel sensitivity
Cyclin A-associated kinase activity is needed for paclitaxel sensitivity
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DOI：
10.1158/1535-7163.mct-04-0282
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发表时间：
2005-07-01
影响因子：
5.7
通讯作者：
Ueno, NT
中科院分区：
文献类型：
--
作者：
Takahashi, T;Yamasaki, F;Ueno, NT
细胞周期蛋白A相关激酶，如细胞周期蛋白依赖性激酶2（CDK 2），参与调节细胞从G（1）到S到G（2）的进程，CDK 2也参与有丝分裂的过渡。CDK抑制剂单独或与紫杉烷类联合使用的抗肿瘤特性目前正在临床试验中进行检查。在这里，我们研究了与细胞周期蛋白A（如CDK 2）相关的激酶的活性是否在决定细胞对紫杉醇（紫杉烷和有丝分裂抑制剂，用于乳腺癌和卵巢癌化疗）的敏感性方面很重要。我们使用腺病毒抑制或过表达来操纵CDK 2和细胞周期蛋白A在一个乳腺癌和三个卵巢癌细胞系中的表达，这些细胞系对紫杉醇具有不同的敏感性，并评估蛋白表达、激酶活性、细胞周期分布和对紫杉醇的敏感性。显性阴性（DN）-CDK 2的转染通过CDK 1活性的丧失阻止细胞向有丝分裂的进展而诱发对紫杉醇的抗性。在DN-CDK 2转染的癌细胞中野生型CDK 2的再表达恢复了CDK 2活性，但没有恢复紫杉醇敏感性。然而，DN-CDK 2转染细胞中细胞周期蛋白A的表达恢复了它们对紫杉醇的敏感性。虽然CDK 2活性不直接参与紫杉醇敏感性，但细胞周期蛋白A相关激酶确实通过磷酸化上调CDK 1。我们的结论是，细胞周期蛋白A相关激酶活性是必需的这些细胞进入有丝分裂和紫杉醇诱导的细胞死亡。将紫杉烷化疗与任何靶向细胞周期蛋白A相关激酶的药物（例如，纯的CDK 2抑制剂），因为有可能增强紫杉烷类药物的耐药性，所以即使使用也要谨慎。
Cyclin A-associated kinases, such as cyclin-dependent kinase 2 (CDK2), participate in regulating cellular progression from G(1) to S to G(2), and CDK2 has also been implicated in the transition to mitosis. The antitumor properties of CDK inhibitors, alone or in combination with taxanes, are currently being examined in clinical trials. Here, we examined whether the activity of kinases associated with cyclin A (such as CDK2) is important in determining cellular sensitivity to paclitaxel, a taxane and mitotic inhibitor used in chemotherapy for breast and ovarian cancer. We used adenoviral suppression or overexpression to manipulate the expression of CDK2 and cyclin A in one breast cancer and three ovarian cancer cell lines with different sensitivities to paclitaxel and assessed protein expression, kinase activity, cell cycle distribution, and sensitivity to paclitaxel. Transfection of a dominant-negative (DN)-CDK2 evoked resistance to paclitaxel by preventing cellular progression to mitosis through loss of CDK1 activity. Reexpression of wild-type CDK2 in DN-CDK2-transfected cancer cells restored CDK2 activity but not paclitaxel sensitivity. However, expression of cyclin A in DN-CDK2-transfected cells restored their sensitivity to paclitaxel. Although CDK2 activity was not directly involved in paclitaxel sensitivity, cyclin A-associated kinases did up-regulate CDK1 via phosphorylation. We conclude that cyclin A-associated kinase activity is required for these cells to enter mitosis and undergo paclitaxel-induced cell death. Combining taxane chemotherapy with any drug targeting cyclin A-associated kinases (e.g., pure CDK2 inhibitors) should be done with caution, if at all, because of the potential for enhancing taxane resistance.