Lung cancer is the most common and lethal malignant disease for which the development of efficacious chemotherapeutic agents remains an urgent need. Pristimerin (PRIS), a natural bioactive component isolated from various plant species in the Celastraceae and Hippocrateaceae families, has been reported to exhibit outstanding antitumor effects in several types of cells. However, the underlying mechanisms involved remain poorly understood. Here, we reported the novel finding that PRIS significantly suppressed lung cancer growth in conditionally reprogrammed patient-derived lung adenocarcinoma cells (CRLCs). We demonstrated that PRIS inhibited the cell viabilities, migrative and invaded abilities, and capillary structure formation of CRLCs. Furthermore, our results clarified that PRIS induced mitochondrial dysfunction through reactive oxygen species (ROS) generation, activation of caspase-9, caspase-3, and caspase-4, and expression of endoplasmic reticulum (ER) stress-associated proteins. Inhibition of ER stress by 4-PBA (4-phenylbutyric acid, a specific ER stress inhibitor) or CHOP siRNA transfection ameliorated PRIS-induced loss of mitochondrial membrane potential and intrinsic apoptosis. The present study also provides mechanistic evidence that PRIS suppressed the EphB4/CDC42/N-WASP signaling pathway, which is required for mitochondrial-mediated intrinsic apoptosis, activation of ER stress, and stimulation of caspase-4 induced by PRIS, and consequently resulting in suppressed cell viability, migration, and angiogenesis in CRLCs. Taken together, by providing a mechanistic insight into the modulation of ER stress-induced cell death in CRLCs by PRIS, we suggest that PRIS has a strong potential of being a new antitumor therapeutic agent with applications in the fields of human lung adenocarcinoma.

中文翻译：

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Pristimerin通过加重线粒体损伤和内质网应激，通过EphB4 / CDC42 / N-WASP信号传导加重有条件重新编程的患者来源的肺腺癌细胞中的细胞损伤。

肺癌是最常见的致死性恶性疾病，迫切需要开发有效的化学治疗剂。据报道，Pristimerin（PRIS）是从Celestraceae和Hippocrateaceae家族的各种植物中分离出来的天然生物活性成分，在多种类型的细胞中均表现出出色的抗肿瘤作用。但是，所涉及的潜在机制仍知之甚少。在这里，我们报道了一项新发现，即PRIS在有条件重新编程的患者来源的肺腺癌细胞（CRLC）中显着抑制了肺癌的生长。我们证明了PRIS抑制了CRLCs的细胞活力，迁移和侵袭能力以及毛细血管结构的形成。此外，我们的研究结果表明，PRIS通过活性氧（ROS）的产生，caspase-9，caspase-3和caspase-4的激活以及内质网（ER）应激相关蛋白的表达诱导线粒体功能障碍。4-PBA（4-苯基丁酸，一种特定的ER应激抑制剂）或CHOP siRNA转染抑制ER应激可改善PRIS诱导的线粒体膜电位丧失和固有凋亡。本研究还提供了机制证据，表明PRIS抑制了EphB4 / CDC42 / N-WASP信号传导途径，这是线粒体介导的内在凋亡，ER应力激活和PRIS诱导的caspase-4刺激所必需的，从而导致抑制CRLC中的细胞活力，迁移和血管生成。在一起