Graduate Institute of Integrated Medicine, China Medical University, Taichung, 404, Taiwan.
Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung, 404, Taiwan.
Sci Rep. 2017 Jan 30;7:41437. doi: 10.1038/srep41437.
Hepatocellular carcinoma (HCC) remains the leading cause of cancer mortality with limited therapeutic targets. The endoplasmic reticulum (ER) plays a pivotal role in maintaining proteostasis in normal cells. However, alterations in proteostasis are often found in cancer cells, making it a potential target for therapy. Polygonum bistorta is used in traditional Chinese medicine owing to its anticancer activities, but the molecular and pharmacological mechanisms remain unclear. Using hepatoma cells as a model system, this study demonstrated that P. bistorta aqueous extract (PB) stimulated ER stress by increasing autophagosomes but by blocking degradation, followed by the accumulation of ubiquitinated proteins and cell apoptosis. In addition, an autophagy inhibitor did not enhance ubiquitinated protein accumulation whereas a reactive oxygen species (ROS) scavenger diminished both ubiquitinated protein accumulation and ligand-stimulated epidermal growth factor receptor (EGFR) expression, suggesting that ROS generation by PB may be upstream of PB-triggered cell death. Nevertheless, PB-exerted proteostasis impairment resulted in cytoskeletal changes, impairment of cell adhesion and motility, and inhibition of cell cycle progression. Oral administration of PB delayed tumour growth in a xenograft model without significant body weight loss. These findings indicate that PB may be a potential new alternative or complementary medicine for HCC.
肝细胞癌 (HCC) 仍然是癌症死亡的主要原因，治疗靶点有限。内质网 (ER) 在维持正常细胞的蛋白质平衡中起着关键作用。然而，蛋白质平衡的改变在癌细胞中经常被发现，使其成为治疗的潜在靶点。拳参在传统中药中被使用，是因为其具有抗癌活性，但分子和药理学机制仍不清楚。本研究使用肝癌细胞作为模型系统，表明拳参水提物 (PB) 通过增加自噬体但阻止降解来刺激内质网应激，随后导致泛素化蛋白的积累和细胞凋亡。此外，自噬抑制剂不会增强泛素化蛋白的积累，而活性氧 (ROS) 清除剂则减少泛素化蛋白的积累和配体刺激的表皮生长因子受体 (EGFR) 表达，表明 PB 产生的 ROS 可能是 PB 触发细胞死亡的上游事件。然而，PB 引起的蛋白质平衡失调导致细胞骨架改变、细胞黏附和运动受损以及细胞周期进程抑制。PB 的口服给药在没有明显体重减轻的情况下延迟了异种移植模型中的肿瘤生长。这些发现表明，PB 可能是 HCC 的一种有潜力的新的替代或补充药物。
