ROS-mediated activation and mitochondrial translocation of CaMKII contributes to Drp1-dependent mitochondrial fission and apoptosis in triple-negative breast cancer cells by isorhamnetin and chloroquine
ROS-mediated activation and mitochondrial translocation of CaMKII contributes to Drp1-dependent mitochondrial fission and apoptosis in triple-negative breast cancer cells by isorhamnetin and chloroquine
复制标题
ROS 介导的 CaMKII 激活和线粒体易位通过异鼠李素和氯喹促进三阴性乳腺癌细胞中 Drp1 依赖性线粒体裂变和凋亡
DOI：
10.1186/s13046-019-1201-4
复制
发表时间：
2019-05-28
影响因子：
11.3
通讯作者：
Gao, Ning
中科院分区：
文献类型：
--
作者：
Hu, Jinjiao;Zhang, Yanhao;Gao, Ning
背景三阴性乳腺癌（TNBC）通常具有侵袭性，预后不良。由于缺乏可用的靶向治疗和传统的化疗药物的耐药性的问题，寻找新的治疗TNBC仍然是一个挑战，一个更好的治疗策略是迫切需要的。MethodsTNBC细胞和异种移植小鼠进行了治疗与氯喹（CQ）和异鼠李素（IH）的组合。线粒体分裂，细胞凋亡，和相关的信号转导途径进行了测定流式细胞术，免疫荧光，和相关的分子生物学technology.ResultsThe抑制自噬/线粒体自噬CQ选择性增强IH诱导的线粒体分裂和凋亡TNBC细胞，但不是在雌激素依赖性乳腺癌细胞。这些事件伴随着Bax的线粒体易位和细胞色素c的释放。从机制上讲，这些作用与氧化应激介导的CaMKII（Thr 286）和Drp 1（S616）磷酸化以及随后的CaMKII和Drp 1线粒体易位有关。通过遗传方法（例如CaMKII突变体或siRNA）中断CaMKII途径减弱组合介导的线粒体分裂和凋亡。CQ/IH的组合是一个显着的肿瘤生长抑制剂，诱导细胞凋亡的TNBC异种移植小鼠模型与激活的CaMKII和Drp 1（S616）.ConclusionsOur研究突出了ROS介导的CaMKII/Drp 1信号转导在调节线粒体分裂和细胞凋亡的CQ/IH组合诱导的关键作用。这些研究结果也表明，IH有可能进一步发展为一种新的化疗药物。此外，IH与经典的自噬/线粒体自噬抑制剂的组合可以代表用于治疗TNBC的新的治疗策略。
BackgroundTriple-negative breast cancer (TNBC) is often aggressive and associated with a poor prognosis. Due to the lack of available targeted therapies and to problems of resistance with conventional chemotherapeutic agents, finding new treatments for TNBC remains a challenge and a better therapeutic strategy is urgently required.MethodsTNBC cells and xenograft mice were treated with a combination of chloroquine (CQ) and isorhamnetin (IH). Mitochondrial fission, apoptosis, and related signaling pathways were determined by flow cytometry, immunofluorescence, and related molecular biological techniques.ResultsThe inhibition of autophagy/mitophagy by CQ selectively enhances IH-induced mitochondrial fission and apoptosis in TNBC cells but not in estrogen-dependent breast cancer cells. These events were accompanied by mitochondrial translocation of Bax and the release of cytochrome c. Mechanistically, these effects were associated with oxidative stress-mediated phosphorylation of CaMKII (Thr286) and Drp1 (S616), and subsequent mitochondrial translocation of CaMKII and Drp1. The interruption of the CaMKII pathway by genetic approaches (e.g. CaMKII mutant or siRNA) attenuated combination-mediated mitochondrial fission and apoptosis. The combination of CQ/IH was a marked inhibitor tumor growth, inducing apoptosis in the TNBC xenograft mouse model in association with the activation of CaMKII and Drp1 (S616).ConclusionsOur study highlights the critical role of ROS-mediating CaMKII/Drp1 signaling in the regulation of mitochondrial fission and apoptosis induced by combination of CQ/IH. These findings also suggest that IH could potentially be further developed as a novel chemotherapeutic agent. Furthermore, a combination of IH with classic autophagy/mitophagy inhibitor could represent a novel therapeutic strategy for the treatment of TNBC.