Bortezomib inhibits docetaxel-induced apoptosis via a p21-dependent mechanism in human prostate cancer cells
Bortezomib inhibits docetaxel-induced apoptosis via a p21-dependent mechanism in human prostate cancer cells
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DOI：
10.1158/1535-7163.mct-05-0437
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发表时间：
2006-08-01
影响因子：
5.7
通讯作者：
McConkey, David J.
中科院分区：
文献类型：
--
作者：
Canfield, Steven E.;Zhu, Keyi;McConkey, David J.
Bortezomib(PS-341，VELCADE)是一种20S蛋白酶体的多肽硼酸盐抑制剂，目前正与紫杉烷联合用于前列腺癌患者的几项临床试验。在这里，我们报道了硼替佐米抑制多西紫杉醇诱导的雄激素依赖的LNCaP-PRO5细胞的M期停滞和凋亡。直接分析免疫复合体中的激酶活性表明，多西紫杉醇激活了细胞周期蛋白依赖性激酶(CDK)1(CDC2)，而Bortezomib阻断了这种激活。Bortezomib的作用与p21的积累有关，并被化学CDK抑制剂模拟，或通过用针对CDK1的小干扰RNA结构导入细胞来模拟。瞬时转染p21也可抑制多西紫杉醇诱导的细胞凋亡；反之，p21沉默可逆转硼替佐米对多西紫杉醇诱导的细胞凋亡的拮抗作用。总之，我们的数据显示，Bortezomib通过与CDK1抑制相关的p21依赖机制干扰多西紫杉醇诱导的细胞凋亡。这些观察结果可能对正在进行的bortezomib-docetaxel联合试验以及使用bortezomib和其他细胞周期敏感药物的试验具有重要意义。
Bortezomib (PS-341, Velcade) is a peptide boronate inhibitor of the 20S proteasome that is currently being combined with taxanes in several clinical trials in patients with prostate cancer. Here, we report that bortezomib inhibited docetaxel-induced M-phase arrest and apoptosis in androgen-dependent LNCaP-Pro5 cells. Direct analysis of kinase activity in immune complex kinase assays revealed that docetaxel activated cyclin-dependent kinase (CDK) 1 (CDC2) and that bortezomib blocked this activation. The effects of bortezomib were associated with accumulation of p2l and mimicked by chemical CDK inhibitors or by transfecting cells with a small interfering RNA construct specific for CDK1. Transient transfection with p21 also inhibited docetaxel-induced apoptosis; conversely, p21 silencing reversed the antagonistic effects of bortezomib on docetaxel-induced apoptosis. Together, our data show that bortezomib interferes with docetaxel-induced apoptosis via a p21-dependent mechanism that is associated with CDK1 inhibition. These observations may have important implications for the ongoing bortezomib-docetaxel combination trials as well as trials using bortezomib and other cell cycle-sensitive agents.