Involvement of the Nrf2 pathway in the regulation of pterostilbene-induced apoptosis in HeLa cells via ER stress.
Involvement of the Nrf2 pathway in the regulation of pterostilbene-induced apoptosis in HeLa cells via ER stress.
复制标题
DOI：
10.1254/jphs.14028fp
复制
发表时间：
2014-11
影响因子：
3.5
通讯作者：
Bo Zhang;Xiao-qin Wang;Hanying Chen;Binhua Liu
中科院分区：
文献类型：
--
作者：
Bo Zhang;Xiao-qin Wang;Hanying Chen;Binhua Liu
在各种癌细胞系中，发现HeLa细胞对Pterostilbene（Pte）敏感，Pte是一种富含葡萄和浆果等小水果的化合物。然而，涉及的机制在细胞毒性的Pte尚未得到充分的表征。利用体外生物化学和自由基生物学实验，我们确定了Pte的促凋亡特征，并评估了HeLa细胞凋亡过程中氧化还原应激触发的ER应激水平。这些数据表明，Pte暴露和HeLa细胞凋亡的特征在凋亡形态学，DNA片段化和内在凋亡途径中激活的半胱氨酸天冬氨酸蛋白酶的变化方面具有很强的剂量-反应关系。在药物暴露过程中，细胞内氧化还原稳态的改变，有利于氧化是必要的，导致ER应激相关的细胞凋亡，表现为酶和非酶氧化还原调节剂。在经历晚期凋亡的HeLa细胞中，Nrf 2/ARE下游靶基因的独特表达水平出现统计学显着且呈剂量依赖性增加（P < 0.05），而Pte处理后应用抗氧化剂可以恢复该水平。我们的研究表明，Pte通过氧化还原稳态失衡来缓解ER应激，这是由Nrf 2的后续激活负调控的。
Among the various cancer cell lines, HeLa cells were found to be sensitive to pterostilbene (Pte), a compound that is enriched in small fruits such as grapes and berries. However, the mechanism involved in the cytotoxicity of Pte has not been fully characterized. Using biochemical and free radical biological experiments in vitro, we identified the pro-apoptotic profiles of Pte and evaluated the level of redox stress-triggered ER stress during HeLa cell apoptosis. The data showed a strong dose-response relationship between Pte exposure and the characteristics of HeLa apoptosis in terms of changes in apoptotic morphology, DNA fragmentation, and activated caspases in the intrinsic apoptotic pathway. During drug exposure, alterations in the intracellular redox homeostasis that favor oxidation were necessary to cause ER stress-related apoptosis, as demonstrated by enzymatic and non-enzymatic redox modulators. A statistically significant and dose-dependent increase (P < 0.05) was found with regard to the unique expression levels of Nrf2/ARE downstream target genes in HeLa cells undergoing late apoptosis, levels that were restored with anti-oxidant application with the Pte treatment. Our research demonstrated that Pte trigged ER stress by redox homeostasis imbalance, which was negatively regulated by a following activation of Nrf2.