Proteasome inhibitors decrease paclitaxel‑induced cell death in nasopharyngeal carcinoma with the accumulation of CDK1/cyclin B1.
Proteasome inhibitors decrease paclitaxel‑induced cell death in nasopharyngeal carcinoma with the accumulation of CDK1/cyclin B1.
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DOI：
10.3892/ijmm.2021.5026
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发表时间：
2021-10
影响因子：
5.4
通讯作者：
Jiang B
中科院分区：
文献类型：
--
作者：
Hu L;Pan X;Hu J;Zeng H;Liu X;Jiang M;Jiang B
东南亚是鼻咽癌的高发地区。紫杉醇是治疗晚期鼻咽癌的主要药物。本研究旨在探讨蛋白酶体抑制剂对紫杉醇疗效的影响及其相关机制。细胞计数试剂盒-8和流式细胞术分析的当前数据表明，适当浓度的蛋白酶体抑制剂（30 nM PS341或700 nM MG 132）降低了紫杉醇对鼻咽癌细胞的致死作用。虽然400 nM紫杉醇有效抑制细胞分裂并诱导细胞死亡，但蛋白酶体抑制剂（PS341 30 nM或MG 132 700 nM）可逆转这些作用。此外，蛋白质印迹结果表明细胞周期调节蛋白CDK 1和细胞周期蛋白B1在蛋白酶体修饰物处理的细胞中积累。此外，蛋白酶体抑制剂与紫杉醇联合使用导致由CDK 1/细胞周期蛋白B1触发的MCL 1凋亡调节因子、BCL 2家族成员/Caspase-9/聚（ADP-核糖）聚合酶凋亡信号转导减少。因此，CDK 1/细胞周期蛋白B1的功能障碍可以定义紫杉醇对癌细胞的致死性的丧失，这一现象由CDK 1抑制剂Ro 3306证实。总体而言，目前的结果表明，紫杉醇与蛋白酶体抑制剂或CDK 1抑制剂的组合对NPC的有效临床管理具有拮抗作用。
Southeast Asia is a region with high incidence of nasopharyngeal carcinoma (NPC). Paclitaxel is the mainstay for the treatment of advanced nasopharyngeal cancer. The present study investigated the effect of proteasome inhibitors on the therapeutic effect of paclitaxel and its related mechanism. The present data from Cell Counting Kit-8 and flow cytometry assays demonstrated that appropriate concentrations of proteasome inhibitors (30 nM PS341 or 700 nM MG132) reduced the lethal effect of paclitaxel on the nasopharyngeal cancer cells. While 400 nM paclitaxel effectively inhibited cell division and induced cell death, proteasome inhibitors (PS341 30 nM or MG132 700 nM) could reverse these effects. Additionally, the western blotting results demonstrated accumulation of cell cycle regulation protein CDK1 and cyclin B1 in proteasome inhibitor-treated cells. In addition, proteasome inhibitors combined with paclitaxel led to decreased MCL1 apoptosis regulator, BCL2 family member/Caspase-9/poly (ADP-ribose) polymerase apoptosis signaling triggered by CDK1/cyclin B1. Therefore, dysfunction of CDK1/cyclin B1 could be defining the loss of paclitaxel lethality against cancer cells, a phenomenon affirmed by the CDK1 inhibitor Ro3306. Overall, the present results demonstrated that a combination of paclitaxel with proteasome inhibitors or CDK1 inhibitors is antagonistic to effective clinical management of NPC.