Background:

We evaluated the effect of cabazitaxel (CAB) as a third-line taxane on Toll-like receptor 4 (TLR4)-mediated signaling pathways, especially NF-κB activity, in metastatic castration-resistant prostate cancer (mCRPC) cells.

Methods:

CAB cytotoxicity was determined by WST-1 assay. To assess the relationship between CAB efficacy and TLR4 signaling pathways, RT-PCR, western blot and immunofluorescence analysis were performed. Additionally, CAB-mediated apoptotic cell death was assessed by Annexin V and RT-PCR analysis.

Results:

Our results demonstrated that CAB exerted considerably cytotoxic and apoptotic effects on PC-3 mCRPC cells (p < 0.05). CAB treatment altered TLR4 expression level in a dose-dependent manner. Furthermore, 1 nM CAB treatment significantly induced NF-κB activity through p65 nuclear localization and increased the expression level of caspase-3, Bax and p53. Interestingly, total apoptotic cell death and IRF3 protein levels were increased at 5 nM concentration of CAB despite a decrease in the levels of both NF-κB and pro-apoptotic genes.

Conclusions:

Therefore, NF-κB activity may be a potential target for the efficacy of CAB in mCRPC cells.

中文翻译：

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转移性去势抵抗性前列腺癌细胞中卡巴他赛抗癌功效与Toll样受体4介导信号通路的相关性

背景：

我们评估了卡巴他赛 (CAB) 作为三线紫杉醇对转移性去势抵抗性前列腺癌 (mCRPC) 细胞中 Toll 样受体 4 (TLR4) 介导的信号通路，尤其是 NF-κB 活性的影响。

方法：

CAB 细胞毒性由 WST-1 测定确定。为了评估 CAB 功效与 TLR4 信号通路之间的关系，进行了 RT-PCR、蛋白质印迹和免疫荧光分析。此外，通过膜联蛋白 V 和 RT-PCR 分析评估了 CAB 介导的细胞凋亡。

结果：

我们的结果表明，CAB 对 PC-3 mCRPC 细胞具有相当大的细胞毒性和凋亡作用（p < 0.05）。CAB 治疗以剂量依赖性方式改变了 TLR4 的表达水平。此外，1 nM CAB 处理通过 p65 核定位显着诱导 NF-κB 活性，并增加 caspase-3、Bax 和 p53 的表达水平。有趣的是，尽管 NF-κB 和促凋亡基因的水平下降，但在 5 nM 浓度的 CAB 下，总凋亡细胞死亡和 IRF3 蛋白水平增加。

结论：

因此，NF-κB 活性可能是 CAB 在 mCRPC 细胞中发挥功效的潜在目标。